Cereblon binding compounds, compositions thereof, and methods of treatment therewith

ABSTRACT

Provided herein are piperidine dione compounds having the following structure: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R N , R 1 , R 2 , R 3 , R 4 , R N , L, V, X, a, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/356,370, filed Jun. 23, 2021, which claims the benefit of U.S.Provisional Application No. 63/043,555, filed Jun. 24, 2020, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD

Provided herein are compounds, compositions comprising an effectiveamount of such compounds, and methods for treating or preventingandrogen receptor mediated diseases, comprising administering aneffective amount of such compounds to a subject in need thereof. Alsoprovided herein are the compounds and compositions for use in thesemethods.

BACKGROUND

Androgen receptor signaling is known to play a crucial role in thepathogenesis of prostate cancer and is involved in the development ofother androgen receptor positive cancers (Chen Y et al., Lancet Oncol,2009, 10:981-91; Mills I G, Nat Rev Cancer, 2014, 14:187-98; Taplin M E,Nat Clin Pract Oncol, 2007, 4:236-44; Wirth M P et al., Eur Urol, 2007,51(2):306-13). The inhibition of androgen receptor signaling withanti-androgens that antagonize the androgen receptor has been used orproposed for the treatment of prostate cancer.

The androgen receptor normally resides in the cytoplasm bound tochaperones such as HSP90 (Brinkmann A O et al., J Steroid Biochem MolBiol, 1999, 69:307-13). Upon binding of dihydrotestosterone (DHT) theandrogen receptor changes its conformation and translocates to thenucleus, where it binds androgen responsive elements (AREs) driving thetranscription of canonical targets such as KLK3 (also known as prostatespecific antigen PSA), TMPRSS2 and KLK2 (Tran C et al., Science, 2009,324:787-90; Murtha P et al., Biochemistry (Mosc.), 1993, 32:6459-64).

Prostate cancer (PCa) is one of the most frequently diagnosednon-cutaneous cancers among men in the US and is the second most commoncause of cancer deaths with more than 200,000 new cases and over 30,000deaths each year in the United States.

Androgen-deprivation therapy (ADT) is the standard of treatment foradvanced PCa. Patients with advanced PCa undergo ADT, either byluteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonistsor by bilateral orchiectomy. Despite initial response to ADT, diseaseprogression is inevitable and the cancer emerges as castration-resistantprostate cancer (CRPC). Up to 30% of patients with prostate cancer thatundergo primary treatment by radiation or surgery will developmetastatic disease within 10 years of the primary treatment.Approximately 50,000 patients a year will develop metastatic disease,which is termed metastatic CRPC (mCRPC).

There remains a significant need for safe and effective methods oftreating, preventing and managing AR mediated diseases, particularly forAR mediated diseases that are refractory to standard treatments, such assurgery, radiation therapy, chemotherapy and hormonal therapy, whilereducing or avoiding the toxicities and/or side effects associated withconventional therapies.

Citation or identification of any reference in this section of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

SUMMARY

Provided herein are compounds having the following formula (I).

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein R^(N), R¹, R², R³, R⁴, X, L, V, a, m and nare as defined herein.

A compound of formula (I) or a pharmaceutically acceptable salt,tautomer, isotopolog, or stereoisomer thereof is useful for treating orpreventing androgen receptor mediated diseases in a subject.

In one aspect, provided herein are compounds as described in the instantdisclosure, such as, for example, in Table 1.

In one aspect, provided herein are pharmaceutical compositionscomprising an effective amount of a compound as described herein, and apharmaceutically acceptable carrier, excipient or vehicle. In oneaspect, provided herein are pharmaceutical compositions comprising aneffective amount of a compound as described herein, and apharmaceutically acceptable carrier, excipient or vehicle. In someembodiments the pharmaceutical composition is suitable for oral,parenteral, mucosal, transdermal or topical administration.

In one aspect, provided herein are methods for treating or preventingandrogen receptor mediated diseases in a subject, comprisingadministering to a subject in need thereof an effective amount of acompound as described herein; and a pharmaceutically acceptable carrier,excipient or vehicle. In one aspect, provided herein are methods fortreating or preventing androgen receptor mediated diseases in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound as described herein; and a pharmaceuticallyacceptable carrier, excipient or vehicle. In another aspect, providedherein are compounds for use in methods of treatment of androgenreceptor mediated diseases. In another aspect, provided herein arecompounds for use in methods of treatment of androgen receptor mediateddiseases.

In another aspect provided herein are methods for preparing compounds asdescribed herein. In another aspect provided herein are methods forpreparing compounds as described herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

DETAILED DESCRIPTION Definitions

As used herein, the terms “comprising” and “including” can be usedinterchangeably. The terms “comprising” and “including” are to beinterpreted as specifying the presence of the stated features orcomponents as referred to, but does not preclude the presence oraddition of one or more features, or components, or groups thereof.Additionally, the terms “comprising” and “including” are intended toinclude examples encompassed by the term “consisting of”. Consequently,the term “consisting of” can be used in place of the terms “comprising”and “including” to provide for more specific embodiments of theinvention.

The term “consisting of” means that a subject-matter has at least 90%,95%, 97%, 98% or 99% of the stated features or components of which itconsists. In another embodiment the term “consisting of” excludes fromthe scope of any succeeding recitation any other features or components,excepting those that are not essential to the technical effect to beachieved.

As used herein, the term “or” is to be interpreted as an inclusive “or”meaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, thealkyl group is a saturated alkyl group. Representative saturated alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl,-2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyland the like. In some embodiments, the alkyl group is an unsaturatedalkyl group, also termed an alkenyl or alkynyl group. An “alkenyl” groupis an alkyl group that contains one or more carbon-carbon double bonds.An “alkynyl” group is an alkyl group that contains one or morecarbon-carbon triple bonds. Examples of unsaturated alkyl groupsinclude, but are not limited to, vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂,—C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃),—C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃) and —CH₂C≡C(CH₂CH₃), among others.An alkyl group can be substituted or unsubstituted. When the alkylgroups described herein are said to be “substituted,” they may besubstituted with any substituent or substituents as those found in theexemplary compounds and embodiments disclosed herein, as well ashalogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy,heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(═O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino,heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino,aralkylamino, heterocyclylalkylamino, heteroaralkylamino,heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino;acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino;alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido;nitro; thio (—SH), alkylthio; ═S; sulfinyl; sulfonyl; aminosulfonyl;phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido;cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or —B(OH)2. Incertain embodiments, when the alkyl groups described herein are said tobe “substituted,” they may be substituted with any substituent orsubstituents as those found in the exemplary compounds and embodimentsdisclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro);alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro;cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl;sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane;oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substituted.In some embodiments, the cycloalkyl group has 3 to 8 ring members,whereas in other embodiments the number of ring carbon atoms ranges from3 to 5, 3 to 6, or 3 to 7. In some embodiments, the cycloalkyl groupsare saturated cycloalkyl groups. Such saturated cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike, or multiple or bridged ring structures such as1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, adamantyl and the like. In other embodiments, thecycloalkyl groups are unsaturated cycloalkyl groups. Examples ofunsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. Acycloalkyl group can be substituted or unsubstituted. Such substitutedcycloalkyl groups include, by way of example, cyclohexanol and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aromatic ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl(e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl,pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl(e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridylor 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl),tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Aheteroaryl group can be substituted or unsubstituted.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocycloalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl)groups. The phrase heterocyclyl includes fused ring species, includingthose comprising fused aromatic and non-aromatic groups, such as, forexample, 1- and 2-aminotetraline, benzotriazolyl (e.g.,1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, andbenzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ringsystems containing a heteroatom such as, but not limited to,quinuclidyl. Representative examples of a heterocyclyl group include,but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl,pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl orimidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g.,benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl),morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g.,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g.,indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl,isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl),indazolyl, indolizinyl, benzotriazolyl (e.g.1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl,benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl,benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl (for example,1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl(e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl,isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one andtetrahydroquinolinyl groups. Representative non-aromatic heterocyclylgroups do not include fused ring species that comprise a fused aromaticgroup. Examples of non-aromatic heterocyclyl groups include aziridinyl,azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g.,imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl,piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl,tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl,oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl,quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representativesubstituted heterocyclyl groups may be mono-substituted or substitutedmore than once, such as, but not limited to, pyridyl or morpholinylgroups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstitutedwith various substituents such as those listed below.

As used herein and unless otherwise specified, a “cycloalkylalkyl” groupis a radical of the formula: -alkyl-cycloalkyl, wherein alkyl andcycloalkyl are defined above. Substituted cycloalkylalkyl groups may besubstituted at the alkyl, the cycloalkyl, or both the alkyl and thecycloalkyl portions of the group. Representative cycloalkylalkyl groupsinclude but are not limited to cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyland the like.

As used herein and unless otherwise specified, an “aralkyl” group is aradical of the formula: -alkyl-aryl, wherein alkyl and aryl are definedabove. Substituted aralkyl groups may be substituted at the alkyl, thearyl, or both the alkyl and the aryl portions of the group.Representative aralkyl groups include but are not limited to benzyl andphenethyl groups and aralkyl groups wherein the aryl group is fused to acycloalkyl group such as indan-4-yl ethyl.

As used herein and unless otherwise specified, a “heterocyclylalkyl”group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyland heterocyclyl are defined above. A “heteroarylalkyl” group is aradical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroarylare defined above. A “heterocycloalkylalkyl” group is a radical of theformula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl aredefined above. Substituted heterocyclylalkyl groups may be substitutedat the alkyl, the heterocyclyl, or both the alkyl and the heterocyclylportions of the group. Representative heterocylylalkyl groups includebut are not limited to morpholin-4-yl ethyl, morpholin-4-yl propyl,furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl,tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

A “halogen” is fluorine, chlorine, bromine or iodine.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amino” group is a radical of the formula: —NH₂, —NH(R^(#)), or—N(R^(#))₂, wherein each R^(#)is independently an alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl orheterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl orheterocycloalkylalkyl) group defined above, each of which isindependently substituted or unsubstituted.

In one embodiment, an “amino” group is an “alkylamino” group, which is aradical of the formula: —NH-alkyl or —N(alkyl)₂, wherein each alkyl isindependently defined above. The term “cycloalkylamino”, “arylamino”,“heterocyclylamino”, “heteroarylamino”, “heterocycloalkylamino”, or thelike, mirrors the above description for “alkylamino” where the term“alkyl” is replaced with “cycloalkyl”, “aryl”, “heterocyclyl”,“heteroaryl”, “heterocycloalkyl”, or the like, respectively.

A “carboxy” group is a radical of the formula: —C(O)OH.

As used herein and unless otherwise specified, an “acyl” group is aradical of the formula: —C(O)(R^(#)) or —C(O)H, wherein R^(#)is definedabove. A “formyl” group is a radical of the formula: —C(O)H.

As used herein and unless otherwise specified, an “amido” group is aradical of the formula: —C(O)—NH₂, —C(O)—NH(R^(#)), —C(O)—N(R^(#))₂,—NH—C(O)H, —NH—C(O)—(R^(#)), —N(R^(#))—C(O)H, or —N(R^(#))—C(O)—(R^(#)),wherein each R^(#)is independently defined above.

In one embodiment, an “amido” group is an “aminocarbonyl” group, whichis a radical of the formula: —C(O)—NH₂, —C(O)—NH(R^(#)),—C(O)—N(R^(#))₂, wherein each R^(#)is independently defined above.

In one embodiment, an “amido” group is an “acylamino” group, which is aradical of the formula: —NH—C(O)H, —NH—C(O)—(R^(#)), —N(R^(#))—C(O)H, or—N(R^(#))—C(O)—(R^(#)), wherein each R^(#)is independently definedabove.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#)are defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(O)N(R^(#))₂,—N(alkyl)C(O)NH(R^(#)), —N(alkyl)C(O)NH₂, —NHC(O)N(R^(#))₂,—NHC(O)NH(R^(#)), or —NH(CO)NH₂, wherein each alkyl and R^(#)areindependently as defined above.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl,piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fusedor non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl,benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy;heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of thecompounds of formula (I) include, but are not limited to metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methyl-glucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples ofspecific salts thus include hydrochloride formic, and mesylate salts.Others are well known in the art, see for example, Remington'sPharmaceutical Sciences, 18^(th) eds., Mack Publishing, Easton Pa.(1990) or Remington: The Science and Practice of Pharmacy, 19^(th) eds.,Mack Publishing, Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereoisomerically pure” means one stereoisomer of a compoundprovided herein that is substantially free of other stereoisomers ofthat compound. For example, a stereoisomerically pure compound havingone chiral center will be substantially free of the opposite enantiomerof the compound. A stereoisomerically pure compound having two chiralcenters will be substantially free of other diastereomers of thecompound. A typical stereoisomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,or greater than about 97% by weight of one stereoisomer of the compoundand less than about 3% by weight of the other stereoisomers of thecompound. The compounds can have chiral centers and can occur asracemates, individual enantiomers or diastereomers, and mixturesthereof. All such isomeric forms are included within the embodimentsdisclosed herein, including mixtures thereof.

The use of stereoisomerically pure forms of such compounds, as well asthe use of mixtures of those forms, are encompassed by the embodimentsdisclosed herein. For example, mixtures comprising equal or unequalamounts of the enantiomers of a particular compound may be used inmethods and compositions disclosed herein. These isomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); Wilen,S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972); Todd,M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation:Fundamentals and Practical Methods (Springer Science & Business Media,2007); Subramanian, G. Chiral Separation Techniques: A PracticalApproach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methodsfor Pharmaceutical and Biotechnological Products (John Wiley & Sons,2011).

It should also be noted the compounds can include E and Z isomers, or amixture thereof, and cis and trans isomers or a mixture thereof. Incertain embodiments, the compounds are isolated as either the E or Zisomer. In other embodiments, the compounds are a mixture of the E and Zisomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of compounds of formula (I) are within the scope of thepresent invention.

It should also be noted the compounds provided herein can containunnatural proportions of atomic isotopes at one or more of the atoms.For example, the compounds may be radiolabeled with radioactiveisotopes, such as for example tritium (H), iodine-125 (¹²⁵I), sulfur-35(³⁵S), or carbon-14 (¹⁴C), or may be isotopically enriched, such as withdeuterium (²H), carbon-13 (¹³C), or nitrogen-15 (⁵N). As used herein, an“isotopologue” is an isotopically enriched compound. The term“isotopically enriched” refers to an atom having an isotopic compositionother than the natural isotopic composition of that atom. “Isotopicallyenriched” may also refer to a compound containing at least one atomhaving an isotopic composition other than the natural isotopiccomposition of that atom. The term “isotopic composition” refers to theamount of each isotope present for a given atom. Radiolabeled andisotopically enriched compounds are useful as therapeutic agents, e.g.,cancer therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds as described herein, whetherradioactive or not, are intended to be encompassed within the scope ofthe embodiments provided herein. In some embodiments, there are providedisotopologues of the compounds, for example, the isotopologues aredeuterium, carbon-13, and/or nitrogen-15 enriched compounds. As usedherein, “deuterated”, means a compound wherein at least one hydrogen (H)has been replaced by deuterium (indicated by D or ²H), that is, thecompound is enriched in deuterium in at least one position.

It is understood that, independently of stereoisomerical or isotopiccomposition, each compound referred to herein can be provided in theform of any of the pharmaceutically acceptable salts discussed herein.Equally, it is understood that the isotopic composition may varyindependently from the stereoisomerical composition of each compoundreferred to herein. Further, the isotopic composition, while beingrestricted to those elements present in the respective compound or saltthereof, may otherwise vary independently from the selection of thepharmaceutically acceptable salt of the respective compound.

It should be noted that if there is a discrepancy between a depictedstructure and a name for that structure, the depicted structure is to beaccorded more weight.

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder is an androgen receptor mediateddisease, as described herein, or a symptom thereof.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition. In one embodiment, thedisorder is an androgen receptor mediated disease, as described herein,or symptoms thereof.

The term “effective amount” in connection with a compound means anamount capable of treating or preventing a disorder, disease orcondition, or symptoms thereof, disclosed herein.

The terms “subject” and “patient” as used herein include an animal,including, but not limited to, an animal such a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.In one embodiment, a subject is a human having or at risk for having anandrogen receptor mediated disease, or a symptom thereof.

The term “androgen receptor” or “AR” or “NR3C4” as used herein refers toa nuclear hormone receptor activated by binding of the androgenichormones, including testosterone or dihydrotestosterone. The term“androgen receptor” may refer to the nucleotide sequence or proteinsequence of human androgen receptor (e.g., Entrez 367, Uniprot P10275,RefSeq NM_000044, or RefSeq NP_000035).

The term “AR-full length” (AR-FL) as used herein refers to AR proteinthat contains all four functional domains, including the N-terminaltransactivation domain (NTD, exon 1), the DNA-binding domain (DBD, exons2-3), the hinge domain (exon 4), and the C-terminal ligand bindingdomain (LBD, exons 4-8).

The term “castration resistant prostate cancer” (CRPC) refers toadvanced prostate cancer that is worsening or progressing while thepatient remains on androgen deprivation therapy or other therapies toreduce testosterone, or prostate cancer which is considered hormonerefractory, hormone naive, androgen independent or chemical or surgicalcastration resistant. Castration resistant prostate cancer (CRPC) is anadvanced prostate cancer that developed despite ongoing ADT and/orsurgical castration. Castration resistant prostate cancer is defined asprostate cancer that continues to progress or worsen or adversely affectthe health of the patient despite prior surgical castration, continuedtreatment with gonadotropin releasing hormone agonists (e.g.,leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens(e.g., bicalutamide, flutamide, enzalutamide, ketoconazole,aminoglutethamide), chemotherapeutic agents (e.g., docetaxel,paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine,cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib(Iressa®), cabozantinib (Cometriq®, also known as XL184)) or otherprostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge®),GVAX, etc.), herbal (PC-SPES) and lyase inhibitor (abiraterone)) asevidenced by increasing or higher serum levels of prostate specificantigen (PSA), metastasis, bone metastasis, pain, lymph nodeinvolvement, increasing size or serum markers for tumor growth,worsening diagnostic markers of prognosis, or patient condition.

Compounds

Provided herein are compounds having the following formula (I):

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein:

R^(N) is H;

n is 0-4;

each R¹ is independently selected from halogen, CN, and C₁₋₃ alkyl;

a is 1 or 2;

R² and R³ are each independently selected from H, and C₁₋₃ alkyl, or R²and R³ and the carbon to which they are attached form a substituted orunsubstituted C₃₋₆ cycloalkyl;

m is 0-8;

each R⁴ is independently substituted or unsubstituted C₁₋₃ alkyl, or twoR⁴ groups, together with the same carbon atom or adjacent carbon atomsto which they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl, or two R⁴ groups together with the non-adjacent carbon atomsto which they are attached form a substituted or unsubstituted4-7-membered heterocyclyl;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alk

L is substituted or unsubstituted —O(C₁₋₆ alkyl)-, (C₁₋₆ alkyl)O—,—O(C₁₋₆ alkyl)O—, or —(C₁₋₉ alkyl)-;

V is

wherein

B is N, CH, or CR^(B);

each R^(B) is independently selected from halogen, and substituted orunsubstituted C₁₋₆ alkyl;

R^(C) is halogen, CF₃ or SF₅;

R⁵ and R⁶ are C₁₋₃ alkyl, or R⁵ and R⁶, together with the carbon atom towhich they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl or a 3-6 membered heterocyclyl; and

b is 0-2.

Provided herein are compounds having the following formula (I):

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein:

R^(N) is H;

n is 0-4;

each R¹ is independently selected from halogen, CN, and C₁₋₃ alkyl;

a is 1 or 2;

R² and R³ are each independently selected from H, and C₁₋₃ alkyl, or R²and R³ and the carbon to which they are attached form a substituted orunsubstituted C₃₋₆ cycloalkyl;

m is 0-8;

each R⁴ is independently substituted or unsubstituted C₁₋₃ alkyl, or twoR⁴ groups, together with the same carbon atom or adjacent carbon atomsto which they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl, or two R⁴ groups together with the non-adjacent carbon atomsto which they are attached form a substituted or unsubstituted4-7-membered heterocyclyl;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alk

L is substituted or unsubstituted —O(C₁₋₆ alkyl)-, (C₁₋₆ alkyl)O—, or—(C₁₋₉ alkyl)-;

V is

wherein

B is N, CH, or CR^(B);

each R^(B) is independently selected from halogen, and substituted orunsubstituted C₁₋₆ alkyl;

R^(C) is halogen, CF₃ or SF₅;

R⁵ and R⁶ are C₁₋₃ alkyl, or R⁵ and R⁶, together with the carbon atom towhich they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl or a 3-6 membered heterocyclyl; and

b is 0-2.

In some embodiments of compounds of formula (I), n is 0. In someembodiments of compounds of formula (I), a is 1, and R² and R³ are bothH. In some embodiments of compounds of formula (I), each R⁴ issubstituted or unsubstituted methyl. In some embodiments of compounds offormula (I), each R⁴ is independently selected from methyl and CF₃. Insome embodiments of compounds of formula (I), m is 0, 1, 2, 3 or 4. Insome embodiments of compounds of formula (I), m is 1 or 2. In someembodiments of compounds of formula (I), X is N. In some embodiments ofcompounds of formula (I), X is CR^(X), where R^(X) is hydrogen, halogen,—O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl).

In some embodiments of compounds of formula (I), L is substituted orunsubstituted —O(CH₂)_(p)—, —O(CH₂)_(p)O— or —(CH₂)_(p)—, and p is 1-4.In some embodiments of compounds of formula (I), L is substituted orunsubstituted —O(CH₂)_(p)— or —(CH₂)_(p)—, and p is 1-4. In someembodiments of compounds of formula (I), L is substituted orunsubstituted —O(CH₂)_(p)—, —O(CH₂)_(p)O— or —(CH₂)_(p)—, and p is 2 or3. In some embodiments of compounds of formula (I), L is substituted orunsubstituted —O(CH₂)_(p)—, and p is 2 or 3. In some embodiments ofcompounds of formula (I), L is substituted or unsubstituted —(CH₂)_(p)—,and p is 3 or 4.

In some embodiments of compounds of formula (I), L is —O(CH₂)(CH₂)—,—O(CH₂)(CH₂)(CH₂)—, —O(CH₂)(CH₂)O—, —(CH₂)(CH₂)—, —(CH₂)(CH₂)(CH₂)—, or—(CH₂)(CH₂)(CH₂)(CH₂)—. In some embodiments of compounds of formula (I),L is —O(CH₂)(CH₂)—, —O(CH₂)(CH₂)(CH₂)—, —(CH₂)(CH₂)—, —(CH₂)(CH₂)(CH₂)—,or —(CH₂)(CH₂)(CH₂)(CH₂)—. In some embodiments of compounds of formula(I), L is —O(CH₂)(CH₂)— or —(CH₂)(CH₂)(CH₂)—.

In some embodiments of compounds of formula (I), B is CH. In someembodiments of compounds of formula (I), B is N. In some embodiments ofcompounds of formula (I), b is 0. In some embodiments of compounds offormula (I), R^(C) is CF₃, Cl or SF₅. In some embodiments of compoundsof formula (I), R^(C) is CF₃. In some embodiments of compounds offormula (I), R⁵ and R⁶ are methyl.

In some embodiments of compounds of formula (I), the compound is

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

each R^(4m) is independently hydrogen or substituted or unsubstitutedmethyl, wherein the substituents, when present are selected from 1 to 5halo;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, —O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

In some embodiments of compounds of formula (I), the compound is

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

In some embodiments of compounds of formula (I), the compound is

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

In some embodiments of compounds of formula (I), (II), (III) and (IV), nis 0; X is N or CR^(X), R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or—(C₁₋₉ alkyl); L is substituted or unsubstituted —O(CH₂)_(p)— or—(CH₂)_(p)—, p is 1-4; B is CH or N; b is 0; R^(C) is CF₃, Cl or SF₅;R^(C) is CF₃; and R⁵ and R⁶ are methyl.

In some embodiments of compounds of formula (I), (II), (III) and (IV), Lis —O(CH₂)(CH₂)—, —O(CH₂)(CH₂)(CH₂)—, —O(CH₂)(CH₂)O—, —(CH₂)(CH₂)—,—(CH₂)(CH₂)(CH₂)—, or —(CH₂)(CH₂)(CH₂)(CH₂)—. In some embodiments ofcompounds of formula (I), (II), (III) and (IV), L is —O(CH₂)(CH₂)—,—O(CH₂)(CH₂)(CH₂)—, —(CH₂)(CH₂)—, —(CH₂)(CH₂)(CH₂)—, or—(CH₂)(CH₂)(CH₂)(CH₂)—.

Further embodiments provided herein include any combination of one ormore of the particular embodiments set forth above.

In some embodiments of compounds of formula (I), the compound is acompound from Table 1.

The compounds set forth in Table 1 were tested in the AR mediated assaysdescribed herein and were found to have activity therein. In oneembodiment, the compounds described herein, at a concentration of 1 μM,leads to degradation of AR protein, by at least about 50% or more.

Methods for Making Piperidine Dione Compounds

The compounds described herein can be made using conventional organicsyntheses and commercially available starting materials, or the methodsprovided herein. By way of example and not limitation, compounds offormula (I), wherein R^(N), R¹, R², R³, R⁴, R⁵, R⁶, R^(B), R^(C), L, V,X, n, m, a and b are as defined herein, can be prepared as outlined inthe schemes shown below, as well as in the examples set forth herein. Itshould be noted that one skilled in the art would know how to modify theprocedures set forth in the illustrative schemes and examples to arriveat the desired products.

As shown in Scheme 1, compounds of formula (I), wherein X is N or CR^(X)and L is —O(C₁₋₃ alkyl)-, —(C₁₋₃ alkyl)O—, or —(C₁₋₄ alkyl)- can beprepared starting by reacting the piperidine derivative a with esterintermediate b (where LG is a leaving group such as Cl, Br, I triflateor alkyl sulfonate, and alk is an alkyl group such as Me, Et, Bn, ortert-Bu) in the presence of a base, in a solvent (for example,N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile) at elevatedtemperature (for example, between about 40° C. and about 100° C.) toprovide intermediate c. In some cases, an iodide salt is used tofacilitate this transformation (such as sodium iodide or potassiumiodide). Removal of the ester protecting group from intermediate c (forexample when alk=Me, Et or other alkyl, by treatment with a hydroxidebase in a solvent, for example LiOH in THE and water, or whenalk=tert-butyl, by treatment with an acid in a solvent such astrifluoroacetic acid in dichloromethane or hydrochloric acid in1,4-dioxane), provides intermediate d. Coupling of intermediate d with apiperidine dione intermediate e in the presence of a coupling agent (forexample HATU, HBTU, or EDC or TCFH, optionally in combination withHOBt), and a base (for example N,N-diisopropylethylamine, triethylamine,or N-methylimidazole), in a solvent, for example, DCM, DMF, NMP ormixtures thereof) at a temperature between 0° C. to about 70° C.provides compounds of formula (I), wherein X is N or CR^(X) and L is—O(C₁₋₃ alkyl)-, —(C₁₋₃ alkyl)O—, or —(C₁₋₄ alkyl)-. Alternatively, forintermediate c wherein X is N and L is —O(C₁₋₃ alkyl)- or —(C₁₋₄ alkyl)-can be prepared starting by reacting the derivative V-L-LG (LG is anappropriate leaving group such as Cl, Br, I, triflate or alkylsulfonate) with an appropriately derivatized piperidyl ester derivativef (for example, wherein alk is an alkyl group such as Me, Et, Bn, ortert-Bu) in the presence of a base, in a solvent (for example,N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile), at elevatedtemperature (for example, between about 40° C. and about 80° C.) toprovide intermediate c.

Compounds of formula (I) wherein X is N and L is —O(C₁₋₃ alkyl)- or—(C₁₋₄ alkyl)- can also be prepared according to an alternative sequenceshown in Scheme 2 by reacting the derivative V-L-LG (LG is anappropriate leaving group such as Cl, Br, I, triflate or alkylsulfonate) with an appropriately derivatized piperidyl derivative g inthe presence of a base, in a solvent (for example,N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile) at elevatedtemperature (for example, between about 40° C. and about 100° C.). Insome cases, an iodide salt is used to facilitate this transformation(such as sodium iodide or potassium iodide). Alternatively, compounds offormula (I) wherein X is N or CR^(X) and L is —O(C₁₋₃ alkyl)-, —(C₁₋₃alkyl)O—, or —(C₁₋₄ alkyl)- can be prepared starting by reactingcompound e with an appropriately functionalized carbonyl intermediate h(where LG is a leaving group such as Cl, Br, I triflate or alkylsulfonate) in the presence of a base, in a solvent (for example,N,N-diisopropylethylamine in DCM, or triethylamine in pyridine) at atemperature between 0° c. to about 60° C. to provide intermediate i.Reacting i (where LG is a leaving group such as Cl, Br, I triflate oralkyl sulfonate) with amine intermediate a in the presence of a base, ina solvent (for example, N,N-diisopropylethylamine in DMF, or K₂CO₃ inacetonitrile), at elevated temperature (for example, between about 40°C. and about 80° C.) provides compound of formula (I) wherein X is N orCR^(X) and L is —O(C₁₋₃ alkyl)-, —(C₁₋₃ alkyl)O—, or —(C₁₋₄ alkyl)-.

Intermediates such as amine g can pe prepared according to Scheme 3.Starting by reacting an appropriately functionalized piperazine j withester intermediate b (where LG is a leaving group such as Cl, Br, Itriflate or alkyl sulfonate, and alk is an alkyl group such as Me, Et,Bn, or tert-Bu) in the presence of a base, in a solvent (for example,N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile) at elevatedtemperature (for example, between about 40° C. and about 100° C.) toprovide intermediate k. In some cases, an iodide salt is used tofacilitate this transformation (such as sodium iodide or potassiumiodide). Removal of the ester protecting group from intermediate k (forexample when alk=Me, Et or other alkyl, by treatment with a hydroxidebase in a solvent, for example LiOH in THE and water, or whenalk=tert-butyl, by treatment with an acid in a solvent such astrifluoroacetic acid in dichloromethane or hydrochloric acid in1,4-dioxane), provides intermediate l. Coupling of intermediate l with apiperidine dione intermediate e in the presence of a coupling agent (forexample HATU, HBTU, or EDC or TCFH, optionally in combination withHOBt), and a base (for example N,N-diisopropylethylamine, triethylamine,or N-methylimidazole), in a solvent, for example, DCM, DMF, NMP ormixtures thereof) at a temperature between 0° C. to about 70° C.provides amine intermediate g. Intermediates such as amine f can beprepared by removal of the N-protecting group P^(N) from intermediate k,(for example, when P^(N) is Boc, by treatment with an acid in a solvent,for example, HCl in dioxane or EtOAc, at room temperature, or with TFAin DCM, at room temperature or when P^(N) is Bn or Cbz by hydrogenationwith a metal catalyst, in a solvent such as palladium on carbon inmethanol).

Intermediates such as a wherein X is N and L is —O(C₁₋₃ alkyl)- or—(C₁₋₄ alkyl)- can be prepared according to Scheme 4. Treating V-L-LG(where L is —O(C₁₋₃ alkyl)- or —(C₁₋₄ alkyl)- and LG is a leaving groupsuch as Cl, Br, I triflate or alkyl sulfonate) with amine n in thepresence of a base, in a solvent (for example, N,N-diisopropylethylaminein DMF, or K₂CO₃ in acetonitrile) at elevated temperature (for example,between about 40° C. and about 100° C.) to provide intermediate o. Insome cases, an iodide salt is used to facilitate this transformation(such as sodium iodide or potassium iodide). Removal of the N-protectinggroup P^(N) from intermediate o, (for example, when P^(N) is Boc, bytreatment with an acid in a solvent, for example, HCl in dioxane orEtOAc, at room temperature, or with TFA in DCM, at room temperature orwhen P^(N) is Bn or Cbz by hydrogenation with a metal catalyst, in asolvent such as palladium on carbon in methanol) provides intermediate awherein X is N and L is —O(C₁₋₃ alkyl)- or —(C₁₋₄ alkyl)-.

Intermediates such as V-L-R^(Z) (for example, intermediate r) whereR^(Z) is an alcohol, protected alcohol, leaving group or heterocycle(such as a substituted piperidine or piperazine) can be preparedaccording to Scheme 5. Treatment of ester intermediate p (where alk isan alkyl group such as Me, Et, Bn, or tert-Bu) with an appropriatelyderivatized 4-isothiocyanatobenzonitrile or5-isothiocyanatopicolinonitrile q, in the presence of a base, such astriethylamine, in a solvent, such as EtOAc, at elevated temperature, forexample, between about 70° C. and about 90° C. provides intermediate r.Intermediates such as u wherein LG is a leaving group (such as Cl, Br, Itriflate or alkyl sulfonate), and L is —O(C₁₋₃ alkyl)- or —(C₁₋₄ alkyl)-can be prepared from intermediate s (where P^(O) is an alcoholprotecting group such as THP, TBS, acetate or benzyl). Removal of theprotecting group P^(O) (for example, when P^(O) is THP by treatment withcatalytic acid in a solvent, for example HCl in dioxane) in s providesalcohol intermediate t. Activation of the alcohol functional group in tto a leaving group (for example when LG is Br by treatment of t withthionyl bromide in dichloromethane) provides intermediate u wherein LGis a leaving group (such as Cl, Br, I triflate or alkyl sulfonate), andL is —O(C₁₋₃ alkyl)- or —(C₁₋₄ alkyl)-, which can be further reacted toprovide compounds of formula (I).

Intermediates p, wherein L is —O(C₁₋₃ alkyl)- and R^(Z) is a protectedalcohol OP^(O) (for example a THP ether or TBS ether), for example aa,can be prepared according to Scheme 6. Starting from alcoholintermediate v (where P^(N) is an amine protecting group such as Bn orBoc), reacting with electrophile w (where LG is a leaving group such asCl, Br, I triflate or alkyl sulfonate, and P^(O) is an oxygen protectinggroup such as THP or TBS) in the presence of a base, optionally with acatalyst, in a solvent (for example KOH and tetrabutylammonium bromidein xylene) at elevated temperature, for example between 70° C. and 130°C. provides intermediate x. Removal of the protecting group P^(N) in x(for example, when P^(N) is Bn by hydrogenation with palladium on carbonin methanol, or when P^(N) is Boc by treatment with HCL in dioxane)provides amine intermediate y. Reacting amine y with ester z (where alkis an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leavinggroup such as Cl, Br, I triflate or alkyl sulfonate) in the presence ofa base, possibly with an iodide salt, in a solvent (for example,potassium carbonate and potassium iodide in acetonitrile), at anelevated temperature (for example between about 70° C. and 130° C.)provides intermediate aa, which can be further reacted to providecompounds of formula (I) where in L=—O(C₁₋₃ alkyl)-.

Intermediates p, wherein L is —(C₁₋₃ alkyl)- and R^(Z) is an alcohol ora protected alcohol (for example a THP ether or TBS ether), for examplehh, can be prepared according to Scheme 6. Starting from aldehydeintermediate bb (where P^(N) is an amine protecting group such as Bn orBoc), reacting with an olefination reagent, in the presence of a base,in a solvent (for example, ethyl 2-(diethoxyphosphoryl)acetate andsodium hydride in THF) at a temperature between 0° C. and 60° C.provides olefin intermediate cc. Reduction of cc by hydrogenation, inthe presence of a catalyst, in a solvent (for example, palladium oncarbon in methanol under a hydrogen atmosphere), at elevated pressure(for example between 10 and 100 psi) provides intermediate dd. Reductionof the ester functional group can be accomplished by treatment with areducing agent, in a solvent (for example, diisobutylaluminum hydride inDCM) at a temperature between −78° C. and 25° C. provides intermediateee, wherein R^(Y) is H. Alternatively, intermediate ee can be preparedby treatment of intermediate cc with a reducing agent, in a solvent (forexample, diisobutylaluminum hydride in DCM) at a temperature between−78° C. and 25° C. to provide intermediate ff. Hydrogenation of ff, inthe presence of a catalyst, in a solvent (for example, palladium oncarbon, in methanol, under a hydrogen atmosphere), at elevated pressure(for example between 10 and 100 psi) provides intermediate ee. Removalof the protecting group P^(N) in ee (for example, when P^(N) is Bn, byhydrogenation with palladium on carbon in methanol, or when P^(N) is Bocby treatment with HCL in dioxane) provides amine intermediate gg.Reacting amine gg with ester z (where alk is an alkyl group such as Me,Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I triflateor alkyl sulfonate) in the presence of a base, optionally with an iodidesalt, in a solvent (for example, potassium carbonate and potassiumiodide in acetonitrile), at an elevated temperature (for example betweenabout 70° C. and 130° C.) provides intermediate hh, where R^(Y) is H oran alcohol protecting group (for example THP, TBS or Tr) which can befurther reacted to provide compounds of formula (I) where in L —(C₁₋₃alkyl)-.

Intermediates p wherein L is —(C₁₋₃ alkyl)O— and R^(Z) is a heterocycleor cycloalkyl group, for example mm, can be prepared according to Scheme8. Starting from intermediate ii (where P^(N′) is an amine protectinggroup for example Bn or Boc), and LG is a leaving group, for example Cl,Br, I triflate or alkyl sulfonate), reacting with alcohol jj (whereP^(N) is an amine protecting group for example Bn or Boc), in thepresence of a base, optionally with a catalyst, in a solvent (forexample KOH and tetrabutylammonium bromide in xylene) at elevatedtemperature (for example between 70° C. and 130° C.), provides etherintermediate kk. Removal of the protecting group P^(N′) in kk (forexample, when P^(N′) is Bn, by hydrogenation with palladium on carbon inmethanol, or when P^(N) is Boc by treatment with HCl in dioxane)provides amine intermediate ll.

Reacting amine 11 with ester z (where alk is an alkyl group such as Me,Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I triflateor alkyl sulfonate) in the presence of a base, optionally with an iodidesalt, in a solvent (for example, potassium carbonate and potassiumiodide in acetonitrile), at an elevated temperature (for example betweenabout 70° C. and 130° C.) provides intermediate mm, which can be furtherreacted to provide compounds of formula (I) wherein L is —(C₁₋₃alkyl)O—.

For certain intermediates p wherein L is —O(C₁₋₃ alkyl)- and R^(Z) is aprotected heterocycle or cycloalkyl group, for example qq, a modifiedsequence can be used, shown in Scheme 9. Starting from alcohol v(wherein P^(N) is an amine protecting group such as Bn or Boc), reactiong with electrophile intermediate nn (where LG is a leaving group, forexample Cl, Br, I, triflate or alkyl sulfonate, and P^(N′) is an amineprotecting group such as Bn or Boc) in the presence of a base,optionally with a catalyst, in a solvent (for example KOH andtetrabutylammonium bromide in xylene) at elevated temperature (forexample between 70° C. and 130° C.), provides ether intermediate oo.Removal of the protecting group P^(N) in oo (for example, when P^(N′) isBn, by hydrogenation with palladium on carbon in methanol, or when P^(N)is Boc by treatment with HCl in dioxane) provides amine intermediate pp.Reacting amine pp with ester z (where alk is an alkyl group such as Me,Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I triflateor alkyl sulfonate) in the presence of a base, optionally with an iodidesalt, in a solvent (for example, potassium carbonate and potassiumiodide in acetonitrile), at an elevated temperature (for example betweenabout 70° C. and 130° C.) provides intermediate qq, which can be furtherreacted to provide compounds of formula (I) wherein L is —O(C₁₋₃alkyl)-.

Certain examples of intermediates nn wherein X is CR^(Z), for examplevv, were prepared according to Scheme 10. Olefination of ketoneintermediate rr, wherein P^(N) is an amine protecting group (for exampleBn, Boc, or Cbz) with an olefination reagent and a base, in a solvent(for example, ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride inTHF) at a temperature between 0° C. and 60° C. provides olefinintermediate ss. Hydrogenation of ss, in the presence of a catalyst, ina solvent (for example, palladium on carbon in methanol under a hydrogenatmosphere), at elevated pressure (for example between 10 and 100 psi)provides intermediate tt. Reduction of the ester functional group in ttis accomplished by treatment with a reducing agent, in a solvent (forexample, diisobutylaluminum hydride in DCM) at a temperature between−78° C. and 25° C. provides intermediate uu. Activation of the alcoholuu to a leaving group LG (for example, if LG is Br, by treatment withthionyl bromide in dichloromethane and DMF, or if LG is triflate, bytreatment with triflic anhydride in dichloromethane) providesintermediate vv, which can be further reacted to provide compounds offormula (I) wherein L is —O(C₁₋₃ alkyl)- and X is CR^(X).

Appropriately derivatized 3-((3-aminophenyl)amino)piperidine-2,6-dionese are prepared from R¹-derivatized 3-nitroanilines ww, which areprotected with an amine protecting group P^(N) (wherein when P^(N) is,for example Boc, by treatment with Boc₂O in the presence of a base, suchas TEA, DIEA, or DBU, in a solvent, such as THF, NMP or DMF) to formintermediate xx. The nitro group in intermediate xx is reduced (bytreatment with a reducing agent, for example H₂, in the presence of acatalyst, such as Pd/C, in a solvent, such as EtOH or MeOH; or Fe andNH₄Cl, in a solvent such as EtOH and H₂O) to provide the mono-protectedderivatized dianiline intermediate yy. Coupling of intermediate yy with3-bromopiperidine-2,6-dione in the presence of a base, in a solvent (forexample, NaHCO₃, CsCO₃, or K₂CO₃, in DMF or NMP, at elevatedtemperature, for example between about 50° C. and about 80° C.; or DIEAin DMF or NMP, at elevated temperature, for example, about 150° C.),followed by removal of the protecting group P^(N)(for example, whenP^(N) is Boc, treatment with an acid, in a solvent, such as TFA in DCM;or treatment with HCl in dioxane or EtOAc) provides intermediate e.Alternatively, intermediate e is obtained via iron-catalyzed reductivecoupling of intermediate xx and 3-bromopiperidine-2,6-dione (forexample, by reaction in the presence of Zn, TMSCl, FeCl₂*4H₂O, in asolvent, such as NMP, at elevated temperature, for example between about80° C. to about 100° C.), followed by removal of the protecting groupP^(N) (for example, when P^(N) is Boc, treatment with an acid in asolvent, such as TFA in DCM; or treatment with HCl in dioxane or EtOAc).

Methods of Use

In one embodiment, the compounds described herein have utility aspharmaceuticals to treat, prevent or improve conditions in animals orhumans. The compounds described herein have utility as pharmaceuticalsto treat, prevent or improve conditions in animals or humans.Accordingly, provided herein are many uses of compounds, including thetreatment or prevention of those diseases set forth below. In oneembodiment, the methods provided herein comprise the administration ofan effective amount of a compound to a subject in need thereof.

The methods provided herein comprise the administration of an effectiveamount of one or more compound(s) to a subject in need thereof.

Provided herein are methods for treating or preventing an androgenreceptor (AR) mediated disease in a subject, the method comprisingadministering to a subject in need thereof an effective amount of acompound as described herein.

Provided herein are methods for treating or preventing an AR mediateddisease in a subject, the method comprising administering to a subjectin need thereof an effective amount of a compound as described herein.

In another aspect, provided herein are compounds for use in thetreatment or prevention of an AR mediated disease in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound as described herein. In some embodiments, providedherein are compounds for use in the treatment of an AR mediated diseasein a subject, comprising administering to a subject in need thereof aneffective amount of a compound as described herein. In some embodiments,provided herein are compounds for use in the prevention of an ARmediated disease in a subject, comprising administering to a subject inneed thereof an effective amount of a compound as described herein.

In some embodiments, the compound used in the methods herein is acompound as described herein. In some embodiments, the compound is acompound of formula (I). In some embodiments, the compound is a compoundof formula (II). In some embodiments, the compound is a compound offormula (III). In some embodiments, the compound is a compound offormula (IV). In some embodiments, the compound is a compound from Table1.

In some embodiments, the AR mediated disease is AR wild-type mediateddisease. In other embodiments, the AR mediated disease is the result ofAR amplification.

In certain embodiments, the AR mediated disease is prostate cancer. Insome such embodiments, the prostate cancer is castration resistantprostate cancer (CRPC). In some such embodiments, the prostate cancer ismetastatic castration resistant prostate cancer (mCRPC). In stillanother embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC).In some embodiments, the prostate cancer is hormone refractory. In someembodiments, the prostate cancer is resistant to treatment with an ARantagonist. For example, the prostate cancer is resistant to treatmentwith enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001,EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

Provided herein are methods of reducing AR levels, the method comprisingadministering to a subject an effective amount of a compound. Alsoprovided herein are compounds for use in methods of reducing AR levelsin a cell in vivo, ex vivo or in vitro, comprising contacting the cellwith an effective amount of a compound. In one embodiment, the cell isin a patient. In one embodiment, the cell is not in a patient. In oneembodiment, provided herein are methods of reducing levels of wild-typeAR within a tumor, the method comprising administering a therapeuticallyeffective amount of a compound, to reduce the level of wild-type ARwithin the tumor. In one embodiment, provided herein are methods ofreducing levels of AR-full length (AR-FL) within a tumor, the methodcomprising administering a therapeutically effective amount of acompound, to reduce the level of AR-full length (AR-FL) within thetumor. In some embodiments, the AR levels are reduced compared to the ARlevels prior to compound administration. In some embodiments, the ARlevels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or99% compared to the AR levels prior to compound administration.

Also provided herein are methods for regulating protein activity of ARin a patient in need thereof, comprising administering to said patientan amount of a compound. In some such embodiments, provided herein aremethods for decreasing protein activity of AR in a patient in needthereof, comprising administering to said patient an amount of acompound. In some embodiments, the protein activity of AR is reducedcompared to the protein activity of AR prior to compound administration.In some embodiments, the protein activity of AR is reduced by 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the proteinactivity of AR prior to compound administration.

In some embodiments of the methods described herein, the methodsadditionally comprise administering one or more second agents selectedfrom an AR antagonist (such as cyproterone acetate, spironolactone,bicalutamide, and enzalutamide), a 5α-reductase inhibitor (such asfinasteride and dutasteride), a CYP17A1 inhibitor (such as abirateroneacetate), a gonadotropin-releasing hormone (GnRH) analog (such asleuprorelin and cetrorelix), and an anti-gonadotropin (such as megestrolacetate and medroxyprogesterone acetate).

In some embodiments, the compounds provided herein may be used in any ofthe above-mentioned methods.

In some embodiments, the compound provided herein may be used in any ofthe above-mentioned methods.

Pharmaceutical Compositions and Routes of Administration

The compounds provided herein can be administered to a subject orally,topically or parenterally in the conventional form of preparations, suchas capsules, microcapsules, tablets, granules, powder, troches, pills,suppositories, injections, suspensions, syrups, patches, creams,lotions, ointments, gels, sprays, solutions and emulsions.

The compounds can be administered to a subject orally, topically orparenterally in the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions, syrups, patches, creams, lotions, ointments,gels, sprays, solutions and emulsions. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g., sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the compounds in the pharmaceutical composition maybe at a level that will exercise the desired effect; for example, about0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject'sbody weight in unit dosage for both oral and parenteral administration.

The dose of a compound to be administered to a subject is rather widelyvariable and can be subject to the judgment of a health-carepractitioner. In general, the compounds can be administered one to fourtimes a day in a dose of about 0.001 mg/kg of a subject's body weight toabout 10 mg/kg of a subject's body weight, but the above dosage may beproperly varied depending on the age, body weight and medical conditionof the subject and the type of administration. In one embodiment, thedose is about 0.001 mg/kg of a subject's body weight to about 5 mg/kg ofa subject's body weight, about 0.01 mg/kg of a subject's body weight toabout 5 mg/kg of a subject's body weight, about 0.05 mg/kg of asubject's body weight to about 1 mg/kg of a subject's body weight, about0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject'sbody weight or about 0.25 mg/kg of a subject's body weight to about 0.5mg/kg of a subject's body weight. In one embodiment, one dose is givenper day. In any given case, the amount of the compound administered willdepend on such factors as the solubility of the active component, theformulation used and the route of administration.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 0.01 mg/day to about 750 mg/day, about 0.1 mg/day to about 375mg/day, about 0.1 mg/day to about 150 mg/day, about 0.1 mg/day to about75 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day toabout 25 mg/day, or about 0.1 mg/day to about 10 mg/day of a compound toa subject in need thereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 0.1 mg and 500 mg, about 1 mg and 250 mg, about 1mg and about 100 mg, about 1 mg and about 50 mg, about 1 mg and about 25mg, or between about 1 mg and about 10 mg of a compound.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 0.1 mg or 100 mg of a compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg,70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg,500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a compound.

An compound can be administered once, twice, three, four or more timesdaily. In a particular embodiment, doses of 100 mg or less areadministered as a once daily dose and doses of more than 100 mg areadministered twice daily in an amount equal to one half of the totaldaily dose.

An compound can be administered orally for reasons of convenience. Inone embodiment, when administered orally, a compound is administeredwith a meal and water. In another embodiment, the compound is dispersedin water or juice (e.g., apple juice or orange juice) or any otherliquid and administered orally as a solution or a suspension.

The compound can also be administered intradermally, intramuscularly,intraperitoneally, percutaneously, intravenously, subcutaneously,intranasally, epidurally, sublingually, intracerebrally, intravaginally,transdermally, rectally, mucosally, by inhalation, or topically to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the health-care practitioner, and can depend in-part uponthe site of the medical condition.

In one embodiment, provided herein are capsules containing a compoundwithout an additional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a compound and a pharmaceutically acceptable carrieror vehicle, wherein a pharmaceutically acceptable carrier or vehicle cancomprise an excipient, diluent, or a mixture thereof. In one embodiment,the composition is a pharmaceutical composition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a compound with a suitablecarrier or diluent and filling the proper amount of the mixture incapsules. The usual carriers and diluents include, but are not limitedto, inert powdered substances such as starch of many different kinds,powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the dye. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a compound as a suppository, typicalbases can be used. Cocoa butter is a traditional suppository base, whichcan be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use.

The effect of the compound can be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the compound can beprepared and incorporated in a tablet or capsule, or as a slow-releaseimplantable device. The technique also includes making pellets ofseveral different dissolution rates and filling capsules with a mixtureof the pellets. Tablets or capsules can be coated with a film thatresists dissolution for a predictable period of time. Even theparenteral preparations can be made long-acting, by dissolving orsuspending the compound in oily or emulsified vehicles that allow it todisperse slowly in the serum.

ENUMERATED EMBODIMENTS

The invention may be defined by reference to the following enumerated,illustrative embodiments.

1. A compound of formula I

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

n is 0-4;

each R¹ is independently selected from halogen, CN, and C₁₋₃ alkyl;

a is 1 or 2;

R² and R³ are each independently selected from H, and C₁₋₃ alkyl, or R²and R³ and the carbon to which they are attached form a substituted orunsubstituted C₃₋₆ cycloalkyl;

m is 0-8;

each R⁴ is independently substituted or unsubstituted C₁₋₃ alkyl, or twoR⁴ groups, together with the same carbon atom or adjacent carbon atomsto which they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl, or two R⁴ groups together with the non-adjacent carbon atomsto which they are attached form a substituted or unsubstituted4-7-membered heterocyclyl;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₆ alkyl)-, —(C₁₋₆ alkyl)O—,—O(C₁₋₆ alkyl)O—, or —(C₁₋₉ alkyl)-;

V is

wherein

B is N, CH, or CR^(B);

each R^(B) is independently selected from halogen, and substituted orunsubstituted C₁₋₆ alkyl;

R^(C) is halogen, CF₃ or SF₅;

R⁵ and R⁶ are C₁₋₃ alkyl, or R⁵ and R⁶, together with the carbon atom towhich they are attached, form a substituted or unsubstituted C₃₋₆cycloalkyl or a 3-6 membered heterocyclyl; and

b is 0-2.

2. The compound of embodiment 1, wherein n is 0.

3. The compound of embodiment 1 or 2, wherein a is 1, and R² and R³ areboth H.

4. The compound of any one of embodiments 1 to 3, wherein each R⁴ issubstituted or unsubstituted methyl.

5. The compound of any one of embodiments 1 to 4, wherein each R⁴ isindependently selected from methyl and CF₃.

6. The compound of any one of embodiments 1 to 5, wherein m is 0, 1, 2,3 or 4.

7. The compound of any one of embodiments 1 to 5, wherein m is 1 or 2.

8. The compound of any one of embodiments 1 to 7, wherein X is N.

9. The compound of any one of embodiments 1 to 7, wherein X is CR^(X),where R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl).

10. The compound of any one of embodiments 1 to 9, wherein L issubstituted or unsubstituted —O(CH₂)_(p)—, —O(CH₂)_(p)O— or —(CH₂)_(p)—,and p is 1-4.

11. The compound of any one of embodiments 1 to 9, wherein L issubstituted or unsubstituted —O(CH₂)_(p)—, and p is 2 or 3.

12. The compound of any one of embodiments 1 to 9, wherein L issubstituted or unsubstituted —(CH₂)_(p)—, and p is 3 or 4.

13. The compound of any one of embodiments 1 to 9, wherein L is—O(CH₂)(CH₂)—, —O(CH₂)(CH₂)(CH₂)—, —O(CH₂)(CH₂)O—, —(CH₂)(CH₂)—,—(CH₂)(CH₂)(CH₂)—, or —(CH₂)(CH₂)(CH₂)(CH₂)—.

14. The compound of any one of embodiments 1 to 9, wherein L is—O(CH₂)(CH₂)— or —(CH₂)(CH₂)(CH₂)—.

15. The compound of any one of embodiments 1 to 14, wherein B is CH.

16. The compound of any one of embodiments 1 to 14, wherein B is N.

17. The compound of any one of embodiments 1 to 16, wherein b is 0.

18. The compound of any one of embodiments 1 to 17, wherein R^(C) isCF₃, Cl or SF₅.

19. The compound of any one of embodiments 1 to 17, wherein R^(C) isCF₃.

20. The compound of any one of embodiments 1 to 19, wherein R⁵ and R⁶are methyl.

21. The compound of embodiment 1, having formula II

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

-   -   each R^(4m) is independently hydrogen or substituted or        unsubstituted methyl, wherein the substituents, when present are        selected from 1 to 5 halo;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, —O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

22. The compound of embodiment 1, having formula III

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, —O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

23. The compound of embodiment 1, having formula IV

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein

R^(N) is H;

X is N or CR^(X);

R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl);

L is substituted or unsubstituted —O(C₁₋₃ alkyl)-, —O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-;

V is

B is N or CH;

R^(C) is halogen, CF₃ or SF₅; and

R⁵ and R⁶ are C₁₋₃ alkyl.

24. The compound of embodiment 1, wherein the compound is selected fromTable 1 or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof.

25. A pharmaceutical composition comprising an effective amount of acompound of any one of embodiments 1 to 24, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, and apharmaceutically acceptable carrier, excipient or vehicle.

26. A method for the treatment of an androgen receptor mediated disease,the method comprising administering to a subject in need thereof aneffective amount of a compound of any one of embodiments 1 to 24.

27. A method for the treatment of an androgen receptor mediated disease,the method comprising administering to a subject in need thereof aneffective amount of the pharmaceutical composition of embodiment 25.

28. The method of embodiment 26 or 27, wherein the androgen mediateddisease is prostate cancer.

29. The embodiment of embodiment 28, wherein the prostate cancer iscastration resistant prostate cancer (CRPC).

EXAMPLES

The following Examples are presented by way of illustration, notlimitation.

Compounds are named using the automatic name generating tool provided inChemBiodraw Ultra (Cambridgesoft), which generates systematic names forchemical structures, with support for the Cahn-Ingold-Prelog rules forstereochemistry. One skilled in the art can modify the procedures setforth in the illustrative examples to arrive at the desired products.

Salts of the compounds described herein can be prepared by standardmethods, such as inclusion of an acid (for example TFA, formic acid, orHCl) in the mobile phases during chromatography purification, orstirring of the products after chromatography purification, with asolution of an acid (for example, aqueous HCl).

Abbreviations used:

DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMAN,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO DimethylsulfoxideESI Electrospray ionization HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate HPLC High performance liquid chromatographyIBX 1-Hydroxy-1λ⁵,2-benziodoxole-1,3-dione LCMS Liquid chromatographymass spectrometry MeOH Methanol MS Mass spectrometry MTBE Methyltert-butyl ether NMP N-Methylpyrrolidone NMR Nuclear magnetic resonanceOMs Mesylate OTs Tosylate PPh3 Triphenylphosphine TFA Trifluoraceticacid Tf₂O Triflic anhydride THF Tetrahydrofuran THP Tetrahydropyrane TLCThin layer chromatography TMSCl Trimethylsilyl chloride TMSCNTrimethylsilyl cyanide TMSOTf Trimethylsilyl trifluoromethanesulfonateTsOH p-Toluenesulfonic acid

Example 1:2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

trans-4-(Dibenzylamino)cyclohexan-1-ol. To a mixture oftrans-4-aminocyclohexane-1-ol (40 g, 347 mmol, 1.0 equiv.) and cesiumcarbonate (339 g, 1.04 mol, 3 equiv.) in acetonitrile (900 mL) was addeddrop wise benzyl bromide (119 g, 698 mmol, 2.01 equiv.). The reactionsolution was stirred at room temperature. After 48 h the reactionmixture was filtered and concentrated. The resulting residue was dilutedwith DCM (300 mL), washed with water (100 mL×3), dried over anhydroussodium sulfate and concentrated. To providetrans-4-(dibenzylamino)cyclohexan-1-ol (77 g, 261 mmol, 75% yield) as alight red solid. The crude product was carried forward without furtherpurification. MS (ESI) m/z 116.3 [M+1]⁺; ¹H NMR 400 MHz DMSO-d₆ δ7.27-7.34 (m, 8H), 7.19-7.21 (m, 2H), 4.42 (d, J=4.8 Hz, 1H), 3.55 (s,4H), 2.33-2.36 (m, 1H), 1.74-1.84 (m, 4H), 1.40 (dd, J=12.4 Hz, 2.0 Hz,2H), 0.98 (d, J=13.2 Hz, 2H).

trans-N,N-Dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine.To a mixture of trans-4-(dibenzylamino)cyclohexan-1-ol (60 g, 203 mmol,1.0 equiv.) and tetrabutylammonium hydrogensulfate (13.8 g, 40.6 mmol,0.2 equiv.) in THE (400 mL) and water (200 mL) was added2-(2-bromoethoxy)tetrahydro-2H-pyran (84.9 g, 406 mmol, 61.5 mL, 2.0equiv.) and sodium hydroxide (200 g, 5.00 mol, 24.6 equiv.) at 0° C. Thereaction solution was heated to 65° C. After 12 h the reaction solutionwas poured into ice-water (1.0 L) and the aqueous phase was extractedwith ethyl acetate (300 mL×2). The combined organic layers were washedwith brine (300 mL), dried with anhydrous sodium sulfate, filtered andconcentrated. The resulting crude material was purified by columnchromatography (SiO₂, 2-50% ethyl acetate in petroleum ether) to givetrans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine(60 g, 142 mmol, 70% yield) as a colorless oil. ¹H NMR 400 MHz CDCl₃ δ7.37-7.39 (m, 4H), 7.28-7.32 (m, 4H), 7.22 (m, 2H), 4.63-4.67 (m, 1H),3.57-3.89 (m, 9H), 3.23-3.25 (m, 1H), 2.55 (m, 1H), 2.08-2.11 (m, 2H),1.92-1.95 (m, 5H), 1.58-1.64 (m, 6H), 1.54-1.56 (m, 2H), 1.20-1.39 (m,2H).

trans-4-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine. Toa mixture oftrans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine(65 g, 153 mmol, 1.0 equiv.) in methanol (500 mL) was added 10%palladium on carbon (6.5 g) under N₂. The suspension was degassed undervacuum and purged with hydrogen gas three times. The reaction solutionwas stirred under an atmosphere of hydrogen gas (15 psi) at roomtemperature. After 1 h the reaction solution was filtered and thefiltrate was concentrated to givetrans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (46g) as an off-white oil. The crude material was carried forward withoutfurther purification. ¹H NMR 400 MHz CDCl₃ δ 7.34-7.36 (m, 1H),4.63-4.65 (m, 1H), 3.82-3.91 (m, 3H), 3.52-3.66 (m, 5H), 3.28 (m, 1H),2.70-2.71 (m, 1H), 2.01-2.04 (m, 2H), 1.85-1.89 (m, 3H), 1.58-1.59 (m,1H), 1.45-1.56 (m, 8H), 1.29-1.32 (m, 2H), 1.11-1.14 (m, 2H).

Methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate.To a mixture oftrans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (25g, 103 mmol, 1.0 equiv.) in acetonitrile (175 mL) was added methyl2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 equiv.),potassium carbonate (28.4 g, 205 mmol, 2.0 equiv.) and potassium iodide(1.71 g, 10.3 mmol, 0.1 equiv.). The reaction solution was heated to110° C. After 16 h the reaction solution was diluted with water (100 mL)and extracted with ethyl acetate (2×75 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfateconcentrated. The resulting crude material was purified by columnchromatography (SiO₂, 0-50% ethyl acetate in petroleum ether) to affordmethyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(18.6 g, 54 mmol, 53% yield) as a yellow oil. MS (ESI) m/z 344.4 [M+1]⁺;¹H NMR (400 MHz CDCl₃) δ 4.63 (t, J=3.2 Hz, 1H), 3.82-3.87 (m, 2H), 3.70(s, 3H), 3.61-3.63 (m, 4H), 3.51-3.60 (m, 2H), 3.22-3.24 (m, 1H), 2.36(m, 1H), 1.99 (m, 2H), 1.83-1.86 (m, 3H), 1.62 (m, 1H), 1.53-1.60 (m,6H), 1.30 (m, 6H), 1.12-1.14 (m, 2H).

4-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(18.6 g, 54.2 mmol, 1.0 equiv.) in ethyl acetate (130 mL) was added4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0equiv.) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equiv.).The reaction solution was heated to 90° C. with stirring. After 12 h thereaction solution was concentrated and the resulting crude material waspurified by silica gel column chromatography (0-50% ethyl acetate inpetroleum ether) to give4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(25 g, 46.3 mmol, 86% yield) as a yellow oil.

4-(3-(trans-4-(2-Hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(42.5 g, 78.8 mmol, 1.0 equiv.) in dichloromethane (300 mL) was added 4M hydrochloric acid in 1,4-dioxane (400 mL) drop-wise. The reactionsolution was stirred at room temperature. After 1 h the reactionsolution was concentrated and purified by silica gel columnchromatography (1-20% THE in dichloromethane) to give4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(21 g, 46.1 mmol, 59% yield) as a yellow glassy oil. MS (ESI) m/z 456.4[M+1]⁺; ¹H NMR (400 MHz CDCl₃) δ 7.95 (d, J=8.0 Hz, 1H), 7.85 (m, 1H),7.72 (dd, J=10.0 Hz, 1.6 Hz, 1H), 3.73-3.77 (m, 4H), 3.60-3.62 (m, 2H),3.37-3.39 (m, 1H), 2.88-2.91 (m, 2H), 2.21-2.24 (m, 2H), 1.97 (m, 1H),1.83-1.88 (m, 3H), 1.61 (s, 6H), 1.33-1.41 (m, 2H).

4-(3-(trans-4-(2-Bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a mixture of4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(3.500 g, 7.72 mmol, 1.0 equiv.) in dichloromethane (80 mL) was addedN,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol,2.0 equiv.) at 0° C. After 12 h the reaction solution was poured intoaqueous saturated sodium bicarbonate solution (100 mL) and extractedwith dichloromethane (3×50 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude material was purified by column chromatography (9-20% ethylacetate in petroleum ether) to give4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(4.200 g, 8.13 mmol, crude) as a yellow solid. MS (ESI) m/z 518.1[M+1]⁺.

tert-Butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. Asolution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5.g, 23.33 mmol, 1 equiv.), methyl bromoacetate (3.57 g, 23.33 mmol, 1equiv.) and triethylamine (10.2 mL, 70 mmol, 3 equiv.) in THE (100 mL,0.23 M) was stirred at 50° C. After 18 h the reaction solution wasdiluted with saturated aqueous sodium bicarbonate (50 mL) and extractedwith ethyl acetate (3×100 mL). the combined organic layers were washedwith brine (50 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude material was purified by silica gelcolumn chromatography (10-100% ethyl acetate in hexanes) to givetert-butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate(6.2 g, 21.6 mmol, 92% yield) as a yellow oil. MS (ESI) m/z 287.2[M+1]⁺.

Methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate. To a solution oftert-butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (1g, 3.49 mmol, 1 equiv.) in dichloromethane (3 mL) was added 4 M HCl in1,4-dioxane (8.7 mL, 34.9 mmol, 10 equiv.) and the reaction solution wasstirred at room temperature. After 2 h the reaction solution wasconcentrated neutralized with aqueous sodium bicarbonate, and extractedwith ethyl acetate (5×50 mL). The combined organic layers were driedover anhydrous magnesium sulfate and concentrated to provide methyl2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (510 mg, 2.72 mmol, 78%yield) as a yellow oil. MS (ESI) m/z 187.5 [M+1]⁺.

Methyl2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate.To a solution of4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(208 mg, 0.400 mmol, 1 equiv.), methyl2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (116 mg,0.520 mmol, 1.3 equiv.) and sodium iodide (79 mg, 0.5200 mmol, 1.3equiv.) was added N,N-dimethylformamide (3.2 mL, 0.13 M) andN,N-diisopropylethylamine (0.17 mL, 0.960 mmol, 2.4 equiv.). Thereaction was stirred at 60° C. After 48 h the reaction solution wasconcentrated and the crude material was purified by silica gel columnchromatography (0-100% ethyl acetate in hexanes) to give methyl2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate(250 mg, 0.40 mmol, 97% yield) as a yellow solid. MS (ESI) m/z 624.0[M+1]⁺.

2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)aceticacid. To a solution of methyl2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate(250 mg, 0.400 mmol, 1 equiv.) in 3:1 water/THF (5 mL) was added lithiumhydroxide (100 mg, 4.17 mmol, 10 equiv.) and the reaction solution wasstirred at room temperature. After 1 h the reaction solution was dilutedwith water and adjusted to pH ˜4 by addition of 1 M hydrochlorid acid.The solution was extracted with ethyl acetate (4×50 mL), and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated to give2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)aceticacid (218 mg, 0.358 mmol, 90% yield) as a pale orange solid. MS (ESI)m/z 610.0 [M+1]⁺.

tert-Butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate. To asolution of tert-butyl N-(3-aminophenyl)carbamate (290 g, 1.39 mol, 1equiv.) and 3-bromopiperidine-2,6-dione (294 g, 1.53 mol, 1.1 equiv.) inN,N-dimethylformamide (1500 mL, 0.93 M) was added sodium bicarbonate(117 g, 1.9 mol, 1.4 equiv.). The reaction mixture was stirred at 80° C.After 16 h the reaction solution was cooled to 25° C. and poured intoice water (4 L), forming a precipitate which was filtered and dried. Thesolid was washed with ethyl acetate/petroleum ether (1:1, 2000 mL) anddried to give tert-butyl(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (400 g, 1.25 mol,90% yield) as a green solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H),9.03 (s, 1H), 6.95-6.83 (m, 2H), 6.67-6.64 (m, 1H), 6.31-6.29 (m, 1H),5.79 (d, J=7.6 Hz, 1H), 4.24-4.20 (m, 1H), 2.73-2.50 (m, 2H), 2.11-2.09(m, 1H), 1.89-1.68 (m, 1H), 1.49 (s, 9H).

3-((3-Aminophenyl)amino)piperidine-2,6-dione. To a suspension oftert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (200 g,626 mmol) in dichloromethane (1500 mL, 0.42 M) was added trifluoroaceticacid (770 g, 6.75 mol, 10.8 equiv.) at 0° C. The reaction solution wasstirred at 25° C. for 16 hrs. The reaction solution was concentrated,and the residue was diluted with methyl tert-butyl ether (2000 mL),stirred for 30 min at room temperature and the formed solid was filteredand dried to give crude product ˜420 g as trifluoroacetate salt. Thesalt was dissolved in water (6 L) and the pH adjusted to 7˜8 by additionof saturated aqueous sodium bicarbonate. The solution was filtered, andthe filtrate was extracted with ethyl acetate (4×1500 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedto give 3-((3-aminophenyl)amino)piperidine-2,6-dione (172 g, 392 mmol,62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 6.73 (t, J=8.0Hz, 1H), 5.91-5.86 (m, 3H), 5.41 (d, J=7.2 Hz, 1H), 4.72 (s, 2H),4.19-4.15 (m, 1H), 2.72-2.51 (m, 2H), 2.09-2.08 (m, 1H), 1.20-1.85 (m,1H).

2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.A mixture of2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)aceticacid (2.500 g, 4.10 mmol, 1.0 eq) and3-((3-aminophenyl)amino)piperidine-2,6-dione (1.079 g, 4.92 mmol, 1.2eq) in N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine(1.590 g, 12.30 mmol, 3 eq) and HATU (2.337 g, 6.15 mmol, 1.5 eq). Thereaction was stirred at 60° C. for 12 hours. The mixture wasconcentrated under vacuum and purified by standard methods to give2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(1.150 g, 14.1 mmol, 35% yield) as a yellow solid. MS (ESI) m/z 811.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 9.33 (s, 1H), 8.33(d, J=8.4 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.6, 8.4 Hz, 1H),7.04-6.93 (m, 2H), 6.81-6.75 (m, 1H), 6.40 (dd, J=1.6, 8.4 Hz, 1H), 5.89(d, J=8.0 Hz, 1H), 4.33-4.23 (m, 1H), 3.92-3.74 (m, 1H), 3.53 (t, J=6.0Hz, 2H), 3.29-3.21 (m, 1H), 3.19 (s, 2H), 2.88-2.55 (m, 8H), 2.41 (br t,J=6.0 Hz, 2H), 2.12-2.02 (m, 3H), 1.92-1.82 (m, 3H), 1.71 (br d, J=10.4Hz, 2H), 1.54 (s, 6H), 1.39-1.25 (m, 2H), 0.96 (d, J=6.0 Hz, 6H).

Example 2:2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

tert-butyl (trans-4-formylcyclohexyl)carbamate. To a mixture oftert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05mol, 1 equiv.) in acetonitrile (1.60 L) was added IBX (352 g, 1.26 mol,1.2 equiv.) at 15° C. The reaction was stirred at 65° C. for 1 h. Thetwo batches were combined for work up and purification. The reactionmixture was filtered and the filter was concentrated in vacuum to givetert-butyl (trans-4-formylcyclohexyl)carbamate (470 g, crude) as a whitesolid. The crude was used for next step directly without furtherpurification. ¹H NMR (400 MHz CDCl₃) δ 9.62 (s, 1H), 4.43 (s, 1H), 4.41(s, 1H), 2.10-2.14 (m, 3H), 2.01-2.05 (m, 2H), 1.45 (s, 9H), 1.38-1.41(m, 2H), 1.14-1.18 (m, 2H).

Ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. Toa mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 equiv.)in THF (900 mL) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate(255 g, 1.14 mol, 1.1 equiv.) drop-wise. The reaction was stirred at 0°C. for 1 h. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate(235 g, 1.03 mol, 1 equiv.) in THE (500 mL) was added drop-wise at 0° C.The reaction was stirred at 25° C. for 2 h. The reaction solution waspoured into ice water (3.0 L) and stirred for 20 min. The aqueous phasewas extracted with ethyl acetate (800 mL, 500 mL). The combined organicphase was washed with brine (500 mL), dried over anhydrous sodiumsulfate and concentrated to give ethyl(E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g,crude) as a light yellow solid. The material was carried forward withoutfurther purification without further purification. ¹H NMR (400 MHzCDCl₃) δ 6.88 (dd, J=15.6 Hz, 6.8 Hz 1H), 5.75-5.79 (m, 1H), 4.40 (s,1H), 4.12-4.23 (m, 3H), 3.39 (s, 1H), 2.04-2.08 (m, 3H), 1.81-1.85 (m,2H), 1.44 (s, 9H), 1.33-1.35 (m, 1H), 1.26-1.30 (m, 6H), 1.10-1.16 (m,3H).

tert-Butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate.Reaction set up as two reactions in parallel. To a solution of compoundethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate(280 g, 942 mmol, 1 equiv.) in dichloromethane (1.12 L) under argonatmosphere at −78° C. was added diisobutylaluminum hydride (1 M, 1.88 L,2 equiv.). The reaction was stirred at −78° C. for 1 h. The reaction wasquenched by MeOH (280 mL) at −60° C. Two reaction mixtures were combinedand poured into sat. citric acid (1.0 kg citric acid in 4.0 L H₂O) below10° C. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). Thecombined organic layers were washed with aqeuous sodium bicarbonate (2.0L), brine (2.0 L), dried over anhydrous sodium sulfate and concentrated.The crude material was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=50/1 to 0/1) to provide tert-butyl((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (420 g,1.645 mol, 87% yield) as a light yellow solid. ¹H NMR (400 MHz CDCl₃) δ5.58-5.60 (m, 2H), 4.39 (s, 1H), 4.06-4.07 (m, 2H), 3.35 (s, 1H),1.80-2.00 (m, 3H), 1.74-1.78 (m, 2H), 1.42 (s, 9H), 1.08-1.20 (m, 4H).

tert-Butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. Four batchesof this reaction were run in parallel. A mixture of tert-butyl((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411mmol, 1 equiv.) and palladium on carbon (10.5 g, 10% purity) in MeOH(600 mL) was degassed and purged with H₂ for 3 times, and then themixture was stirred at 25° C. for 12 h under H₂ (15 psi). The fourbatches were combined for work up and purification. The reactionsolutions were filtered and concentrated under reduced pressure. Thecrude material was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 0/1). tert-butyl(trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (82 g, 19% yield) andtert-butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate (200 g, 48% yield)as white solids. ¹H NMR (400 MHz CDCl₃) δ 4.38 (s, 1H), 3.63 (t, J=6.4Hz, 2H), 3.37 (s, 1H), 1.98-2.01 (m, 2H), 1.60-1.79 (m, 2H), 1.55-1.59(m, 2H), 1.44 (s, 9H), 1.22-1.28 (m, 3H), 0.95-1.05 (m, 4H).

3-(trans-4-Aminocyclohexyl)propan-1-ol hydrochloride. Two reactions werecarried out in parallel. To a solution of tert-butyl(trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (115 g, 447 mmol, 1equiv.) in methanol (200 mL) was added 4 M hydrochloric acid in methanol(500 mL). The reaction was stirred at 15° C. for 6 h. The two batcheswere combined for work up and purification. The reaction solution wasfiltered and concentrated to give 3-(trans-4-aminocyclohexyl)propan-1-olhydrochloride(160 g, 92% yield) as a light yellow solid. The materialwas carried forward without further purification. ¹H NMR (400 MHzDMSO-d₆) δ 8.09 (s, 4H), 4.62 (s, 2H), 3.35 (t, J=6.8 Hz, 2H), 2.87 (d,J=4.4 Hz, 1H), 1.93 (d, J=10.8 Hz, 2H), 1.73 (d, J=12.8 Hz, 2H),1.38-1.42 (m, 2H), 1.29-1.31 (m, 3H), 1.13-1.17 (m, 3H), 0.89-0.92 (m,2H).

Methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate. To amixture of 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (120 g,619 mmol, 1 equiv.) in acetonitrile (750 mL) was added potassiumcarbonate (428 g, 3.10 mol, 5 equiv.) and methyl2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 equiv.). The mixture wasstirred at 110° C. for 12 h. The reaction solution was filtered andconcentrated. The crude material was purified by silica gel columnchromatography (5-100% ethyl acetate in petroleum ether) to give methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g,210 mmol, 34% yield) as a yellow oil. MS (ESI) m/z 258.2 [M+1]⁺.

4-(3-(trans-4-(3-Hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g,210 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile(62.2 g, 273 mmol, 1.3 equiv.) in ethylacetate (350 mL) was addedN,N-diisopropylethylamine (54.2 g, 420 mmol, 2 equiv.). The mixture wasstirred at 80° C. for 12 h. The reaction mixture was concentrated underreduced pressure and purified by column chromatography (10-100% ethylacetate in petroleum ether) to give4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(63 g, 139 mmol, 66% yield) as a yellow solid. ¹H NMR (400 MHz CDCl₃) δ7.94-7.96 (m, 1H), 7.85 (m, 1H), 7.72-7.75 (m, 1H), 3.64-3.67 (m, 2H),2.69 (s, 2H), 1.95 (d, J=12.8 Hz, 2H), 1.84 (d, J=11.2 Hz, 2H), 1.61 (s,7H), 1.29-1.37 (m, 5H), 1.05-1.08 (m, 2H).

4-(3-(trans-4-(3-Bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.820 g, 1.81 mmol, 1 equiv.) in N,N-dimethylformamide (0.800 mL) anddichloromethane (8 mL) was added thionyl bromide (0.752 g, 3.620 mmol, 2equiv.) slowly at 0° C. After 2 h stirring at 0° C., the reactionsolution was concentrated and purified by silica gel columnchromatography (15-25% ethyl acetate in petroleum ether) to give4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS (ESI) m/z 516.1[M+1]⁺.

Methyl2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate.To a solution of4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(500 mg, 0.968 mmol, 1 equiv.) and methyl2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (270 mg, 1.45 mmol, 1.5equiv.) in N,N-dimethylformamide (4.8 mL, 0.2 M) was addedN,N-diisoproplyethylamine (0.46 mL, 4.84 mmol, 5 equiv.) and thereaction solution was stirred at 50° C. After 18 h the reaction solutionwas diluted with ethyl acetate (100 mL) and washed with saturatedaqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organiclayer was dried over anhydrous magnesium sulfate and concentrated. Thecrude material was purified by silica gel column chromatography (1-10%methanol in dichloromethane) to give methyl2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate(487 mg, 0.784 mmol, 81% yield) as a pale yellow oil. MS (ESI) m/z 622.3[M+1]⁺.

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid. To a solution of methyl2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate(500 mg, 0.82 mmol, 1 equiv.), in 5:1 THF/water (4 mL, 0.2 M) was addedlithium hydroxide (59 mg, 2.46 mmol, 3 equiv.). The reaction solutionwas stirred at room temperature. After 12 h the reaction solution wasdiluted with water (10 mL), adjusted to pH 5 by addition of 2 M HCl andextracted with ethyl acetate (4×50 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated to give2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (364 mg, 0.599 mmol, 73% yield) as an off-white solid. MS (ESI) m/z608.4 [M+1]⁺; ¹H NMR (400 MHz CDCl₃) δ 8.33 (d, J=8.0 Hz, 1H), 8.19 (s,1H), 7.97 (d, J=8.4 Hz, 1H), 3.83 (s, 1H), 3.37 (s, 2H), 3.14 (s, 2H),2.89 (s, 2H), 2.73 (s, 2H), 2.40 (s, 2H), 2.00 (s, 2H), 1.81 (d, J=12.0Hz, 2H), 1.72 (d, J=10.4 Hz, 2H), 1.44-1.54 (m, 8H), 1.15-1.19 (m, 3H),1.05-1.08 (m, 2H), 1.01 (d, J=6.4 Hz, 6H).

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (0.200 g, 0.33 mmol, 1.0 eq) and3-((3-aminophenyl)amino)piperidine-2,6-dione (0.108 g, 0.49 mmol, 1.5eq) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine(0.128 g, 0.99 mmol, 3 eq) and HATU (0.188 g, 0.49 mmol, 1.5 eq). Thereaction was stirred at 60° C. for 12 hours. The mixture was purified bystandard procedures to provide2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.108 g, 0.036 mmol, 40% yield) as a yellow solid. MS(ESI) m/z 809.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.09-11.54 (m, 1H),10.79 (s, 1H), 10.63-10.40 (m, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.20 (d,J=1.6 Hz, 1H), 7.97 (dd, J=1.6, 8.4 Hz, 1H), 7.08-7.01 (m, 1H), 6.99 (s,1H), 6.86 (br d, J=8.0 Hz, 1H), 6.47 (dd, J=1.2, 8.4 Hz, 1H), 4.27 (dd,J=4.8, 11.2 Hz, 4H), 3.90-3.63 (m, 4H), 3.36-3.15 (m, 2H), 3.05 (s, 2H),2.82-2.65 (m, 3H), 2.64-2.55 (m, 1H), 2.09 (td, J=4.0, 8.8 Hz, 1H),1.98-1.64 (m, 8H), 1.55 (s, 6H), 1.35 (d, J=1.2 Hz, 6H), 1.28-0.97 (m,6H).

Example 3:2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

(R)-3-((3-aminophenyl)amino)piperidine-2,6-dione and(S)-3-((3-aminophenyl)amino)piperidine-2,6-dione. Racemic3-((3-aminophenyl)amino)piperidine-2,6-dione (8 g) were separated bychiral SFC and the fractions were concentrated at a temperature below35° C. to give two peaks. The absolute configuration was determined byvibrational circular dichroism spectroscopy (VCD).(R)-3-((3-aminophenyl)amino)piperidine-2,6-dione (2.80 g, 35.0% yield,97.7% ee) and (S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (2.90 g,36.3% yield, 97.1% ee) were isolated as brown solids. SFC purificationconditions (Column: Chiralpak IC-H, 250×30 mm i.d. 5 um; mobile phase: Afor CO₂ and B for EtOH:acetonitrile=2:1; gradient: B %=40%; flow rate:75 g/min).

2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a vial containing2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)aceticacid (250 mg, 0.41 mmol, 1 equiv.) was added(R)-3-((3-aminophenyl)amino)piperidine-2,6-dione (107 mg, 0.49 mmol, 1.2equiv.), N,N-dimethylformamide (2.0 mL, 0.1 M), 1-methylimidazole (134mg, 1.64 mmol, 8 equiv.), andN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (230 mg, 0.82 mmol, 4 equiv.). The reaction mixturewas stirred at 25° C. for 90 min. The reaction was taken up in dimethylsulfoxide and purified by semi-prep HPLC using 5-95% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid over 20 min.Fractions containing desired product were combined and volatile organicswere removed under reduced pressure to give a brown solid. The solid wastaken up in acetonitrile:water (1:1) and 1.0 N HCl solution (0.80 mL)was added. The solution was frozen and lyophilized to give2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (139 mg, 0.157 mmol, 38% yield) as a brown solid. MS (ESI)m/z 811.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.34 (d,J=8.31 Hz, 1H), 8.20 (d, J=1.71 Hz, 1H), 7.97 (dd, J=1.71, 8.19 Hz, 1H),7.02-7.09 (m, 1H), 6.99 (br s, 1H), 6.87 (br d, J=7.95 Hz, 1H), 6.47(dd, J=1.47, 8.19 Hz, 1H), 4.27 (dd, J=4.89, 11.37 Hz, 1H), 3.97-4.24(m, 3H), 3.76-3.95 (m, 3H), 3.69 (br s, 2H), 3.22-3.43 (m, 5H),2.68-2.94 (m, 3H), 2.55-2.65 (m, 1H), 2.05-2.17 (m, 3H), 1.91 (dq,J=4.71, 12.12 Hz, 1H), 1.67-1.78 (m, 2H), 1.55 (s, 6H), 1.27-1.45 (m,8H).

Example 4:2-((2R,6S)-4-(2-((trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile.To a solution of methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(2. g, 5.82 mmol, 1 equiv.) in ethyl acetate (1.3234 mL) was added2-chloro-4-isothiocyanatobenzonitrile (2.27 g, 11.65 mmol, 2 equiv.) andN,N-diisopropylethylamine (2.03 mL, 11.65 mmol, 2 equiv.). the reactionsolution was heated to 90° C. with stirring. After 18 h the reactionsolution was concentrated and purified by silica gel columnchromatography (0-50% ethyl acetate in hexanes) to give2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile.(2 g, 3.9521 mmol, 68% yield) as a white solid. MS (ESI) m/z 506.2[M+1]⁺.

2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile.To a solution of2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile(4.0 g, 7.9 mmol, 1 equiv.) was in chloroform (5.7 mL) was added 4 M HClin dioxane (39.52 mL, 158.08 mmol, 20 equiv.) and the reaction solutionwas stirred at room temperature. After 12 h the reaction solution wasconcentrated and purified by silica gel column chromatography (0-40%ethyl acetate in hexanes) to give2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile(1.5 g, 2.883 mmol, 36% yield) as an off white solid. MS (ESI) m/z 422.2[M+1]⁺.

4-(3-(trans-4-(2-Bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile.To a solution of2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile(1.51 g, 3.06 mmol) in dichloromethane (38 mL) and N,N-dimethylformamide(3.8 mL) was added thionyl bromide (0.59 mL, 7.64 mmol, 2.5 equiv.) andthe reaction solution was stirred at room temperature. After 1 h thereaction solution was diluted with ethyl acetate (100 mL) and washedwith saturated aqueous sodium bicarbonate (100 mL), brine (100 mL),dried over anhydrous magnesium sulfate and concentrated. The crudematerial was purified by silica gel column chromatography (0-80% ethylacetate in hexanes) to give4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(1.171 g, 2.42 mmol, 79% yield) as a light yellow solid. MS (ESI) m/z484.0 [M+1]⁺.

2-((2R,6S)-4-(tert-Butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)aceticacid. To a solution of tert-butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate(2.27 g, 7.93 mmol, 1 equiv.) in THE (20 mL) was added lithium hydroxide(208.8 mg, 8.7 mmol, 1.1 equiv.) in water (5 mL), and the reactionsolution was stirred at room temperature. After 18 h the reactionsolution was concentrated under vacuum, and azeotroped three times withchloroform to remove residual water to provide crude2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)aceticacid (2.19 g, 7.8 mmol, 99% yield) as an off-white glassy-solid. Thematerial was carried forward without further purification. MS (ESI) m/z273.2 [M+1]⁺.

tert-Butyl(3S,5R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate.To a solution of2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)aceticacid (2.00 g, 7.34 mmol, 1 equiv.) and3-((3-aminophenyl)amino)piperidine-2,6-dione (1.61 g, 7.34 mmol, 1equiv.) in N,N-dimethylformamide (20 mL) was added HATU (2.79 g, 7.34mmol, 1 equiv.) and N,N-diisopropylethylamine (3.8 mL, 22.03 mmol, 3equiv.) in one portion under nitrogen and the reaction solution wasstirred at 15° C. After 12 h the reaction solution was diluted withwater (800 mL) and extracted with ethyl acetate (100 mL×4). The combinedorganic layers were washed with brine (4×200 mL), dried over anhydroussodium sulfate, filtered and concentrated. The resulting crude materialwas purified by flash silica gel chromatography (0-2% methanol indichloromethane) to give tert-butyl(3S,5R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate(2.45 g, 5.08 mmol, 69% yield) as a light yellow solid. MS (ESI) m/z474.3 [M+1]⁺.

2-((2S,6R)-2,6-Dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of (3R,5S)-tert-butyl4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate(2.30 g, 4.86 mmol, 1 equiv.) in dichloromethane (25 mL) was added 30%hydrogen bromide in acetic acid (2 mL, 14.57 mmol, 3 equiv.) in oneportion under nitrogen and the reaction solution was stirred at 15° C.After 12 h the reaction solution was concentrated to give2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (3.000 g, 6.603 mmol, crude) as a brown solid which wascarried forward without further purification. MS (ESI) m/z 374.3 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 10.47 (br s, 1H), 9.56-9.16(m, 2H), 7.06 (t, J=8.1 Hz, 1H), 6.96 (s, 1H), 6.87 (br d, J=7.9 Hz,1H), 6.53-6.46 (m, 1H), 4.46-4.21 (m, 3H), 3.94 (br s, 2H), 3.58 (br d,J=13.0 Hz, 2H), 2.81-2.69 (m, 1H), 2.81-2.69 (m, 1H), 2.81-2.69 (m, 1H),2.81-2.69 (m, 1H), 2.65-2.54 (m, 1H), 2.14-2.04 (m, 1H), 1.90 (s, 4H),1.34 (br s, 6H).

2-((2R,6S)-4-(2-((trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (179.5 mg, 0.40 mmol, 1.3 equiv.) in N,N-dimethylformamide(3.1 mL, 0.1 M) was added4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(150. mg, 0.31 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.27 mL,1.55 mmol, 5 equiv.), and the reaction solution was heated to 60° C.After 18 h the reaction solution was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers wereconcentrated, filtered and purified by standard methods to give2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (113.2 mg, 0.13 mmol, 42% yield) as an off white solid. MS(ESI) m/z 777.4 [M+1]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.82 (br s, 1H),10.80 (s, 1H), 10.49 (br s, 1H), 8.14 (d, 1H, J=8.2 Hz), 7.93 (d, 1H,J=1.8 Hz), 7.61 (dd, 1H, J=1.8, 8.3 Hz), 7.05 (t, 1H, J=7.4 Hz), 7.00(br s, 1H), 6.87 (br d, 1H, J=7.7 Hz), 6.48 (dd, 1H, J=1.5, 8.2 Hz),4.28 (br dd, 1H, J=4.8, 11.4 Hz), 4.18 (br s, 5H), 3.8-3.9 (m, 3H), 3.71(br dd, 2H, J=4.2, 8.0 Hz), 3.37 (tt, 2H, J=3.7, 10.8 Hz), 3.31 (br s,2H), 2.85 (q, 2H, J=11.6 Hz), 2.75 (ddd, 1H, J=5.2, 12.1, 17.6 Hz), 2.60(td, 1H, J=4.0, 17.5 Hz), 2.11 (td, 3H, J=4.2, 8.4 Hz), 1.92 (dq, 1H,J=4.7, 12.1 Hz), 1.72 (br d, 2H, J=10.8 Hz), 1.54 (s, 6H), 1.3-1.4 (m,8H).

Example 5:2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

5-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.Methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(6.70 g, 19.51 mmol, 1 equiv.),5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.94 g, 39.0 mmol,2 equiv.), and N,N-diisopropylethylamine (6.8 mL, 39.0 mmol, 2 equiv.)were combined in ethyl acetate (56 mL, 0.35 M) and heated to 90° C. in asealed tube for 16 h. The reaction was diluted with ethyl acetate (100mL) and washed with water (100 mL), and brine (100 mL), dried overanhydrous magnesium sulfate and concentrated. The crude material waspurified by silica gel column chromatography (10%-100% ethyl acetate inhexanes) to afford5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m/z 541.3[M+1]⁺.

5-(3-(trans-4-(2-Hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(3.50 g, 6.47 mmol, 1 equiv.) in dichloromethane (30 mL) was added 4 Mhydrochloric acid (16.2 mL, 64.7 mmol, 10 equiv.) and the reactionsolution was stirred at room temperature. After 3 h the reactionsolution was concentrated to provide5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(3.20 g, 6.4 mmol, 99% yield) as a reddish oil. The crude material wascarried forward without further purification. MS (ESI) m/z 457.0 [M+1]⁺.

5-(3-(trans-4-(2-Bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.A solution of5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide(5 mL) was added thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equiv.) andthe reaction solution was stirred at room temperature. After 2 h thereaction solution was concentrated and the crude material was purifiedby silica gel column chromatography (5%-80% ethyl acetate in hexanes) togive5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(2.00 g, 3.85 mmol, 59% yield) as a reddish brown oil. MS (ESI) m/z519.8 [M+1]⁺.

2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride.5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(200 mg, 0.36 mmol),2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (192 mg, 0.47 mmol, 1.3 equiv.), sodium iodide (108 mg,0.72 mmol, 2 equiv.), and N,N-diisopropylethylamine (0.38 mL, 2.16 mmol,6 equiv.) were combined in acetonitrile (1.8 mL, 0.2 M) and heated at60° C. After 7 h the reaction was partitioned between ethyl acetate andwater. The organic layer was washed with brine before drying overmagnesium sulfate, filtering, and concentrating. The crude material waspurified by standard methods. Product fractions were treated with 4 mLof 3M HCl before evaporating to give2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (90 mg, 0.11 mmol, 31% yield) as a white solid. MS (ESI)m/z 812.0 [M+1]+; 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.73-10.84 (m, 1H),9.15 (d, J=1.96 Hz, 1H), 8.75 (d, J=1.96 Hz, 1H), 6.94-7.11 (m, 2H),6.85 (br d, J=7.82 Hz, 1H), 6.46 (br d, J=8.19 Hz, 1H), 4.27 (dd,J=11.31, 4.83 Hz, 1H), 3.85 (br s, 4H), 3.47-3.75 (m, 2H), 3.20-3.43 (m,4H), 2.58-2.95 (m, 4H), 2.03-2.20 (m, 4H), 1.91 (qd, J=12.12, 4.71 Hz,1H), 1.70-1.79 (m, 2H), 1.58 (s, 6H), 1.11-1.48 (m, 7H).

Example 6:2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a 2 dram vial2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (100. mg, 0.16 mmol, 1 equiv.) and(3R)-3-(3-aminoanilino)piperidine-2,6-dione (46.9 mg, 0.21 mmol, 1.3equiv.), added N,N-dimethylformamide (0.55 mL, 0.3 M) and the reactionsolution was stirred until all solids were dissolved. 1-Methylimidazole(0.13 mL, 1.65 mmol, 10 equiv.) followed byN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate(V) (69.25 mg, 0.2500 mmol, 1.5 equiv.) and thereaction solution was stirred at room temperature. After 20 min thereaction solution was diluted with DMSO to a total volume of 4 ml,filtered, and purified by standard methods to give2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (48 mg, 0.059 mmol, 36% yield) as an off-white solid. MS(ESI) m/z 808.4 [M+1]+; 1H NMR (500 MHz, DMSO-d₆) δ 10.77 (s, 1H), 9.41(s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 7.97 (dd, J=1.2, 8.4 Hz,1H), 7.06-6.92 (m, 2H), 6.79 (d, J=8.0 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H),5.89 (d, J=7.6 Hz, 1H), 4.33-4.22 (m, 1H), 3.83 (s, 1H), 3.29-3.19 (m,2H), 2.83-2.66 (m, 5H), 2.64-2.55 (m, 2H), 2.13-2.05 (m, 2H), 1.95-1.67(m, 7H), 1.55 (s, 9H), 1.30-1.05 (m, 7H), 1.01 (s, 6H).

Example 7:2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(pentafluoro-λ⁶-sulfaneyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

4-Bromo-3-(pentafluoro-%⁶-sulfanyl)aniline. To a solution of3-(pentafluoro-λ⁶-sulfanyl)aniline (2.0 g, 9.12 mmol, 1 equiv.) indimethylformamide (15 mL) under a nitrogen atmosphere,N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 equiv.) was added in oneportion at 0° C. The resulting mixture was stirred at room temperaturefor 4 h. The reaction solution was diluted with water (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (100 mL), dried over magnesium sulfate, filteredand concentrated. The crude material was purified by silica gelchromatography (0-20% ethyl acetate in hexanes) to give the4-bromo-3-(pentafluoro-λ⁶-sulfanyl)aniline (1.7 g, 5.7 mmol, 59% yield).¹H NMR (CDCl₃, 400 MHz) δ 7.4-7.5 (m, 1H), 7.1-7.2 (m, 1H), 6.6-6.7 (m,1H), 3.8-4.0 (m, 2H).

4-Amino-2-(pentafluoro-λ⁶-sulfanyl)benzonitrile. A 100 mL round-bottomedflask containing 4-bromo-3-(pentafluoro-λ⁶-sulfanyl)aniline (1.7 g, 5.7mmol, 1 equiv.) and copper(I) cyanide (0.61 g, 6.84 mmol, 1.2 equiv.) inN-methyl pyrrolidinone (30 mL) was heated to 180° C. with stirring.After 4 h the reaction solution was diluted with water (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine. dried over magnesium sulfate and concentrated.The residue was purified by silica gel chromatography (0-20% ethylacetate in hexanes on a 50 g; column) to give4-amino-2-(pentafluoro-λ6-sulfanyl)benzonitrile (1.0 g, 4.09 mmol, 72%yield) as a white solid. MS (ESI) m/z 244.8 [M+1]+.

4-Isothiocyanato-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile. To a 100 mLround-bottomed flask containing thiophosgene (0.94 mL, 12.29 mmol, 1.2equiv.) in water (10 mL) to give an orange solution.4-amino-2-(pentafluoro-λ⁶-sulfanyl)benzonitrile (2.5 g, 10.24 mmol, 1equiv.) in dichloromethane (10 mL) was added. The resulting mixture wasstirred at room temperature for 16 h. The reaction was diluted withwater (100 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine, dried over magnesium sulfate andconcentrated to afford4-isothiocyanato-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile (1.3 g, 4.54mmol, 44% yield) as a white solid which was carried forward withoutfurther purification. MS (ESI) m/z 286.9 [M+1]+.

4-(3-(trans-4-(2-Hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile.To a solution of methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(1.0 g, 2.91 mmol, 1 equiv.) in ethyl acetate (10 mL) was added4-isothiocyanato-2-(pentafluoro-λ⁶-sulfanyl)benzonitrile (1.67 g, 5.82mmol, 1.2 equiv.) and N,N-diisopropylethylamine (1.02 mL, 5.82 mmol, 3equiv.). The reaction solution was stirred at 80° C. After 18 h thereaction solution was concentrated and purified by column chromatography(0-50% ethyl acetate/hexane) to give4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrilea white solid. The intermediate solid was suspended in dichloromethane(1.5 mL), followed by the addition of 4 M hydrochloric acid in dioxane(4 mL, 16 mmol, 3 equiv.), and allowed to stir at 25° C. for 12 h. Thereaction solution was concentrated, the solid was dissolved indichloromethane and purified by silica gel column chromatography (0-40%ethyl acetate in hexane) to afford4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrileas off white solid (0.80 g, 1.33 mmol, 46% yield). MS (ESI) m/z 513.8[M+1]+.

4-(3-(trans-4-(2-Bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile.To a solution of4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile(1.0 g, 1.95 mmol, 1 equiv.) in dichloromethane (30 mL) was addeddimethylformamide (5 mL) and thionyl bromide (1.0 g, 4.87 mmol, 2.5equiv.) sequentially. The reaction solution was stirred at roomtemperature overnight. After 16 h the reaction solution was diluted withbrine (100 mL) and extracted with ethyl acetate (100 mL). The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The crude material was purified by silica gel columnchromatography (0-100% ethyl acetate in hexane) to afford4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile(0.59 g, 1.02 mmol, 53% yield) as a light brown solid. MS (ESI) m/z578.8 [M+1]⁺.

2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(pentafluoro-λ⁶-sulfaneyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a 1-dram vial containing4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ⁶-sulfaneyl)benzonitrile(0.1 g, 0.18 mmol, 1 equiv.),2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.09 g, 0.23 mmol, 1.3 equiv.) and sodium iodide (2.7 mg, 0.02 mmol,0.1 equiv.) added acetonitrile (2 mL) followed byN,N-diisopropylethylamine (0.21 mL, 1.2 mmol, 6 equiv.). The reactionvial was heated with stirring to 60° C. After 16 h the reaction solutionwas diluted to a total volume of 3 ml with dimethylsulfoxide andpurified by standard methods to give2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ⁶-sulfaneyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.05 g, 0.06 mmol, 31% yield) as a yellow solid. MS (ESI)m/z 869.2 [M+1]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.7-10.9 (m, 1H), 8.4-8.5(m, 1H), 8.3-8.4 (m, 1H), 7.9-8.0 (m, 1H), 7.0-7.1 (m, 1H), 7.0-7.0 (m,1H), 6.8-6.9 (m, 1H), 6.4-6.5 (m, 1H), 4.5-4.6 (m, 1H), 4.2-4.3 (m, 4H),3.8-3.9 (m, 4H), 3.57 (s, 5H), 3.4-3.5 (m, 1H), 3.3-3.4 (m, 2H), 2.8-2.9(m, 2H), 2.7-2.8 (m, 1H), 2.5-2.7 (m, 1H), 2.1-2.2 (m, 3H), 1.8-2.0 (m,1H), 1.7-1.8 (m, 2H), 1.5-1.6 (m, 6H), 1.3-1.4 (m, 2H), 1.2-1.3 (m, 6H).

Example 8:2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

3-Chloro-5-isothiocyanato-pyridine-2-carbonitrile. To a solution of5-amino-3-chloro-pyridine-2-carbonitrile (10.00 g, 65.12 mmol, 1 equiv.)in toluene (20 mL) was added thiophosgene (5.96 mL, 78.14 mmol, 1.2equiv.). The mixture was stirred at 110° C. After 16 h the reactionsolution was concentrated and purified by silica gel chromatography(20-50% ethyl acetate in petroleum ether) to give3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (8.000 g, 40.89 mmol,63% yield) as a red solid. MS (ESI) m/z 196.2 [M+1]⁺.

3-Chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile.A mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile(4.000 g, 20.45 mmol, 1 equiv.) and methyl2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate(7.720 g, 22.49 mmol, 1.1 equiv.) in ethyl acetate (100 mL, 0.2 M) wasadded triethylamine (5.7 mL, 40.89 mmol, 2 equiv.). The reactionsolution was stirred at 90° C. After 6 hours the reaction solution wasconcentrated and purified by silica gel column chromatography (10-50%ethyl acetate in petroleum ether) to give3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile(4.000 g, 7.89 mmol, 39% yield) as a yellow solid. MS (ESI) m/z 507.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.92-8.72 (m, 1H), 8.62-8.31 (m,1H), 4.68-4.50 (m, 1H), 3.91-3.63 (m, 4H), 3.62-3.52 (m, 3H), 3.50-3.39(m, 3H), 2.91-2.73 (m, 3H), 2.10-2.03 (m, 2H), 1.75-1.68 (m, 3H), 1.55(s, 6H), 1.50-1.43 (m, 4H).

3-Chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile.To a solution of3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile(4.000 g, 7.89 mmol, 1 equiv.) in methanol (30 mL, 0.27 M) was added 2 Maqueous hydrochloride acid (3 mL, 15.78 mmol, 2 equiv.). The reactionsolution was stirred at 25° C. After 2 h the pH of the mixture wasadjusted to 8 by addition of saturated sodium carbonate. The aqueousphase was extracted with ethyl acetate (250 mL). The combined organiclayers were washed with brine (80 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (33-100% ethylacetate in petroleum ether) to give3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile(2.400 g, 0.01 mmol, 69% yield) as a yellow solid. MS (ESI) m/z 423.3[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.43-7.33 (m, 2H), 7.15(br d, J=7.0 Hz, 1H), 6.57 (br s, 1H), 4.40 (t, J=6.7 Hz, 2H), 2.98 (s,3H), 2.70-2.55 (m, 2H), 1.53 (s, 5H), 1.54-1.51 (m, 1H), 1.54-1.51 (m,1H), 1.54-1.51 (m, 1H), 1.54-1.51 (m, 1H).

5-(3-(trans-4-(2-Bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile.To a solution of3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile(2.150 g, 5.08 mmol, 1 equiv.) in dichloromethane (5 mL, 1 M) andN,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.65 mL,10.17 mmol, 2 equiv.) at 0° C. The mixture was stirred at 25° C. for 16h. The pH of the mixture was adjusted to 8 by saturated sodiumcarbonate. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (50-100% ethyl acetate inpetroleum ether) to give5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile(2.3 g, 4.73 mmol, 93% yield) as a red solid. MS (ESI) m/z 485.1 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.90-8.72 (m, 1H), 8.60-8.44 (m, 1H),3.93-3.81 (m, 1H), 3.79-3.72 (m, 2H), 3.61-3.53 (m, 2H), 3.34 (br s,1H), 2.90-2.74 (m, 2H), 2.12-2.02 (m, 2H), 1.76-1.67 (m, 2H), 1.59-1.52(m, 6H), 1.44-1.28 (m, 2H).

2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a mixture of5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile(0.120 g, 0.25 mmol, 1 equiv.),2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamidehydrobromide (112 mg, 0.25 mmol, 1 equiv.) and sodium iodide (0.004 g,0.02 mmol, 8 mol %) was added N,N-dimethylformamide (4 mL 0.06 M) andN,N-diisopropylethylamine (0.096 g, 0.74 mmol, 3 equiv.). The mixturewas stirred at 60° C. After 16 h the reaction solution was diluted withDMSO (1 mL) and purified by standard methods to give2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.070 g, 0.09 mmol, 36% yield) as a yellow solid. MS(ESI) m/z 778.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.87-10.80 (m, 1H),10.76-10.46 (m, 1H), 8.87-8.74 (m, 1H), 8.58-8.47 (m, 1H), 7.08-7.03 (m,1H), 7.02-6.98 (m, 1H), 6.91-6.86 (m, 1H), 6.52-6.46 (m, 1H), 4.31-4.26(m, 2H), 4.23-4.13 (m, 2H), 3.95-3.81 (m, 6H), 3.43-3.26 (m, 6H),2.94-2.81 (m, 2H), 2.79-2.70 (m, 1H), 2.63-2.56 (m, 1H), 2.17-2.06 (m,3H), 1.97-1.86 (m, 1H), 1.76-1.67 (m, 2H), 1.58-1.53 (m, 6H), 1.43-1.27(m, 8H).

Example 9:2-((2R,6S)-4-(3-((trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

trans-N,N-Dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine.To a solution of trans-4-(dibenzylamino)cyclohexanol (60.00 g, 203.1mmol, 1 equiv.) in xylenes (450 mL, 0.45 M) was added2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5equiv.), tetra-N-butylammonium bromide (13.09 g, 40.62 mmol, 0.2 equiv.)and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 equiv.) and thereaction solution was stirred at room temperature. After 24 h thereaction solution was diluted with ethyl acetate (500 mL) and washedwith water (200 mL), brine (200 mL), dried over anhydrous sodium sulfateand concentrated. The crude material was purified by silica gel columnchromatography (100% petroleum ether) to givetrans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine(40.0 g, 91.4 mmol, 45% yield) as a light yellow oil. MS (ESI) m/z 438.4[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32 (m, 4H), 7.31-7.28 (m, 4H),7.24-7.22 (m, 2H), 4.61-4.57 (m, 1H), 3.88-3.84 (m, 2H), 3.63 (s, 4H),3.55-3.52 (m, 4H), 3.51-3.16 (m, 1H), 2.54-2.09 (m, 1H), 2.08-2.07 (m,2H), 1.92-1.90 (m, 2H), 1.61-1.60 (m, 2H), 1.59-1.57 (m, 6H), 1.55-1.53(m, 2H), 1.38-1.16 (m, 2H)

trans-4-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine. Toa solution oftrans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine(20.0 g, 45.7 mmol, 1 equiv.) in methanol (100 mL) was added 10%palladium on carbon (10.0 g, 9.39 mmol). The reaction flask wasevacuated and purged with hydrogen gas three times and then stirredunder hydrogen atmosphere (15 psi) at room temperature. After 12 h thereaction solution was filtered and the filtrate concentrated to providetrans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine(11.00 g, 42.74 mmol, 94% yield) as a light yellow oil. The material wascarried forward without further purification. ¹H NMR (400 MHz, DMSO-d₆)δ 4.52 (m, 1H), 3.79-3.61 (m, 2H), 3.50-3.30 (m, 4H), 3.18-3.05 (m, 1H),1.94-1.83 (m, 2H), 1.77-1.65 (m, 6H), 1.64-1.55 (m, 1H), 1.53-1.38 (m,4H), 1.20-0.91 (m, 4H).

Methyl2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate.To a solution oftrans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine(7.00 g, 27.2 mmol, 1 equiv.) and methyl 2-bromo-2-methyl-propanoate(12.5 mL, 108.79 mmol, 4 equiv.) in acetonitrile (10 mL) was addedpotassium iodide (0.451 g, 2.72 mmol, 0.1 equiv.) and potassiumcarbonate (7.518 g, 54.4 mmol, 2 equiv.). The reaction vessel was sealedand heated to 110° C. with stirring. After 12 h the reaction solutionwas filtered and concentrated. The crude material was purified by silicagel column chromatography (10-80% ethyl acetate in petroleum ether) togive methyl2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate(8.00 g, 22.4 mmol, 82% yield) as a light yellow oil. MS (ESI) m/z 358.4[M+1]⁺.

2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile.To a solution of methyl2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate(10.0 g, 28.0 mmol, 1 equiv.) in ethyl acetate (100 mL, 0.28 M) wasadded 2-chloro-4-isothiocyanatobenzonitrile (10.9 g, 56.0 mmol, 2equiv.) and triethylamine (7.8 mL, 56.0 mmol, 2 equiv.) and the reactionsolution was stirred at 80° C. After 8 h the reaction solution wasdiluted with water (100 mL) and extracted with ethyl acetate (3×40 mL).The combined organic layers were washed brine (40 mL), dried overanhydrous sodium sulfate and concentrated. The crude material waspurified by silica gel column chromatography (9-20% ethyl acetate inpetroleum ether) to give2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile(8.50 g, 16.3 mmol, 58% yield) as a red oil. MS (ESI) m/z 542.2 [M+23]⁺.

4-(3-(trans-4-(3-Hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile(6.80 g, 13.1 mmol) in methanol (50 mL) was added 1 M hydrochloric acid(5 mL, 13.07 mmol) and the reaction solution was stirred at 25° C. After2 h the reaction solution was diluted with saturated aqueous sodiumbicarbonate (100 mL) and extracted with ethyl acetate (3×50 mL). thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The resulting crude material waspurified by silica gel column chromatography (20-70% ethyl acetate inpetroleum ether) to give4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(5.60 g, 12.8 mmol, 98% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.12 (d, J=8.4 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.61 (dd,J=2.0, 8.4 Hz, 1H), 3.89-3.76 (m, 1H), 3.48-3.42 (m, 4H), 3.24-3.16 (m,1H), 2.79 (d, J=11.2 Hz, 2H), 2.04 (d, J=10.8 Hz, 2H), 1.70 (d, J=10.8Hz, 2H), 1.65-1.59 (m, 2H), 1.53 (s, 6H), 1.34-1.25 (m, 2H).

4-(3-(trans-4-(3-Bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile.To a solution of4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(5.8 g, 13.3 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide(5 mL) was added thionyl bromide (2.1 mL, 26.6 mmol, 2 equiv.) at 0° C.After 8 h the reaction solution was diluted with saturated aqueoussodium bicarbonate (100 mL) and extracted with ethyl acetate (3×40 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The crude material was purified bysilica gel column chromatography (0-35% ethyl acetate in petroleumether) to give4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(4.8 g, 9.6 mmol, 72% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.14-8.11 (m, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.61 (dd, J=1.6,8.0 Hz, 1H), 3.84 (s, 1H), 3.58-3.51 (m, 4H), 3.27-3.21 (m, 1H), 2.81(d, J=11.6 Hz, 2H), 2.06 (m, 2H), 1.71 (d, J=11.6 Hz, 2H), 1.53 (s, 6H),1.33 (d, J=13.2 Hz, 2H).

2-((2R,6S)-4-(3-((trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(0.150 g, 0.300 mmol, 1 equiv.) and2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.168 g, 0.450 mmol, 1.5 equiv.) was added N,N-diisopropylethylamine(0.16 mL, 0.900 mmol, 3 equiv.). The reaction mixture was stirred at 50°C. After 12 h the reaction solution was diluted with water (50 mL) andthe aqueous phase was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The crude materialwas purified by standard methods to give2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.087 g, 0.110 mmol, 37% yield) as a yellow solid. MS(ESI) m/z 791.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.13(d, J=8.4 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.61 (dd, J=1.8, 8.3 Hz, 1H),7.09-7.02 (m, 1H), 6.99 (s, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.48 (d, J=7.9Hz, 1H), 4.28 (dd, J=4.8, 11.3 Hz, 2H), 4.19-4.06 (m, 2H), 3.98-3.63 (m,4H), 3.52 (t, J=5.8 Hz, 2H), 3.30-3.23 (m, 2H), 3.12 (s, 2H), 2.87-2.60(m, 4H), 2.13-1.91 (m, 6H), 1.75-1.68 (m, 2H), 1.53 (s, 6H), 1.42-1.26(m, 8H).

Example 10:2-((2R,6S)-4-(3-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

5-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of methyl2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate(5.00 g, 14.0 mmol, 1 equiv.) and5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g,28.0 mmol, 2 equiv.) in ethyl acetate (50 mL, 0.28 M) was addedN,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 equiv.) and thereaction solution was stirred at 90° C. After 12 h the reaction solutionwas concentrated and purified by silica gel column chromatography(10-50% ethyl acetate in petroleum ether) to give5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(7.00 g, 12.6 mmol, 90% yield) as a brown oil. ¹H NMR (400 MHz, CDCl3) δ8.95 (s, 1H), 8.23 (s, 1H), 4.55-4.51 (m, 1H), 3.81-3.78 (m, 2H),3.70-3.68 (m, 1H), 3.57-3.54 (m, 2H), 3.48-3.45 (m, 2H), 3.29-2.87 (m,1H), 2.85 (d, J=10.8 Hz, 2H), 1.85-1.80 (m, 8H), 1.60 (s, 6H), 1.56-1.52(m, 4H), 1.32-1.29 (m, 2H).

5-(3-(trans-4-(3-Hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(7.00 g, 12.6 mmol, 1 equiv.) in methanol (50 mL) was added 1 M hydrogenchloride (5.0 mL, 5 mmol) and the reaction solution was stirred at roomtemperature. After 2 h the reaction solution was diluted with saturatedaqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and concentrated to give5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(5.00 g, 10.6 mmol, 84% yield) as a brown oil. MS (ESI) m/z 471.2[M+1]⁺.

5-(3-(trans-4-(3-Bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(5.00 g, 10.6 mmol, 1 equiv.) in dichloromethane (50 mL) andN,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3mmol, 2 equiv.) at 0° C. After stirring for 12 h the reaction solutionwas diluted with saturated aqueous sodium bicarbonate (20 mL) andextracted with dichloromethane (2×50 mL). the combined organic layerswere washed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude material was purified by silica gelcolumn chromatography (10-20% ethyl acetate in petroleum ether) to give5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrileas a light yellow solid. (ESI) m/z 535.1 [M+1]⁺; ¹H NMR (400 MHz, CDCl3)δ 8.98 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 3.76-3.65 (m, 1H),3.62 (t, J=5.6 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.40-3.29 (m, 1H), 2.89(s, 2H), 2.30-2.18 (m, 2H), 2.16-2.05 (m, 2H), 1.83 (d, J=12.4 Hz, 2H),1.63 (s, 6H), 1.45-1.24 (m, 2H).

2-((2R,6S)-4-(3-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.150 g, 0.280 mmol, 1 equiv.) and2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (0.128 g, 0.280 mmol, 1 equiv.) in N,N-dimethylformamide (4mL, 0.07 M) was added N,N-diisopropylethylamine (0.24 mL, 1.41 mmol, 5equiv.) and sodium iodide (0.008 g, 0.060 mmol, 2 equiv.) in one portionunder nitrogen. The mixture was stirred at 60° C. After 16 h thereaction solution was diluted with water (80 mL) and extracted withethyl acetate (4×30 mL). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The crude material was purified by standard methods togive2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.089 g, 0.107 mmol, 38% yield) as a yellow solid. MS(ESI) m/z 826.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.76-11.23 (m, 1H),12.31-11.21 (m, 1H), 10.80 (s, 1H), 10.54 (br s, 1H), 9.14 (d, J=1.7 Hz,1H), 8.74 (d, J=2.0 Hz, 1H), 7.08-7.02 (m, 1H), 6.99 (br s, 1H), 6.86(br d, J=7.9 Hz, 1H), 6.50-6.44 (m, 1H), 4.27 (br dd, J=4.8, 11.4 Hz,3H), 4.16 (br s, 3H), 3.92-3.69 (m, 3H), 3.51 (br t, J=5.8 Hz, 2H), 3.26(br t, J=10.6 Hz, 2H), 3.18-3.05 (m, 1H), 3.12 (br s, 1H), 2.90-2.76 (m,1H), 2.90-2.76 (m, 1H), 2.90-2.76 (m, 1H), 2.76-2.68 (m, 1H), 2.64-2.55(m, 1H), 2.14-2.03 (m, 3H), 2.02-1.85 (m, 3H), 1.72 (br d, J=10.3 Hz,2H), 1.57 (s, 6H), 1.44-1.26 (m, 8H).

Example 11:2-((2R,6S)-4-(3-(trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

5-(3-(trans-4-(3-Hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.47g, 5.71 mmol, 1 equiv.) and5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol,1.1 equiv.) in ethyl acetate (15 mL, 0.38 M) was addedN,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equiv.) and thereaction solution was stirred 80° C. After 16 h the reaction solutionwas concentrated under reduced pressure and the crude material waspurified by standard methods to afford5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(1.80 g, 3.96 mmol, 69% yield) as brown solid. MS (ESI) m/z 455.0[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0Hz, 1H), 3.80-3.72 (m, 1H), 3.65 (t, J=6.4 Hz, 2H), 2.72-2.70 (m, 2H),1.97-1.94 (m, 2H), 1.85-1.82 (m, 2H), 1.63 (s, 6H), 1.58-1.54 (m, 1H),1.42-1.29 (m, 4H), 1.12-1.02 (m, 2H).

5-(3-(trans-4-(3-Bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(1.80 g, 3.96 mmol, 1 equiv.) in dichloromethane (18 mL, 0.22 M) andN,N-dimethylformamide (1.8 mL) was added thionyl bromide (1.650 g, 7.92mmol, 2 equiv.) slowly at 0° C. The reaction solution was stirred at 0°C. After 12 h the reaction solution was diluted with water (30 mL) andextracted with dichloromethane (2×25 mL). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated. The cruderesidue was purified by silica gel column chromatography (5-80% ethylacetate in hexanes) to give5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(1.75 g, 3.38 mmol, 85% yield) as brown solid. MS (ESI) m/z 516.9[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0Hz, 1H), 3.80-3.71 (m, 1H), 3.42 (t, J=6.8 Hz, 2H), 2.74-2.72 (m, 2H),1.96-1.79 (m, 6H), 1.63 (s, 6H), 1.40-1.33 (m, 3H), 1.13-1.04 (m, 2H).

2-((2R,6S)-4-(3-(trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.120 g, 0.232 mmol, 1 equiv.) and2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (0.158 g, 0.350 mmol, 1.5 equiv.) in N,N-dimethylformamide(1 mL, 0.23 M) was added N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 5equiv.) in one portion under nitrogen. The mixture was stirred at 50° C.After 12 h the reaction solution was diluted with water (80 mL) andextracted with ethyl acetate (4×30 mL). The combined organic layers werewashed with brine (50 mL), dried over anhydrous sodium sulfate, filteredand concentrated. The crude material was purified by standard methods toprovide2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.129 g, 0.157 mmol, 68% yield) as a yellow solid. MS(ESI) m/z 810.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (br s, 1H),10.80 (s, 1H), 10.64 (br s, 1H), 9.15 (d, J=1.9 Hz, 1H), 8.75 (d, J=2.0Hz, 1H), 7.12-6.96 (m, 2H), 6.88 (br d, J=7.9 Hz, 1H), 6.53-6.44 (m,1H), 6.53-6.44 (m, 1H), 4.32-4.11 (m, 5H), 3.92-3.70 (m, 3H), 3.29 (brs, 2H), 3.06 (br s, 2H), 2.74 (ddd, J=5.1, 12.0, 17.4 Hz, 3H), 2.64-2.55(m, 1H), 2.09 (td, J=4.1, 8.5 Hz, 1H), 1.98-1.88 (m, 1H), 1.87-1.70 (m,6H), 1.57 (s, 6H), 1.38 (br d, J=3.0 Hz, 6H), 1.21 (br d, J=7.1 Hz, 4H),1.16-1.06 (m, 1H), 1.16-1.06 (m, 1H).

Example 12:2-((2R,6S)-4-(3-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

4-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of methyl2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate(5.0 g, 14.0 mmol, 1 equiv.) and4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2equiv.) in ethyl acetate (50 mL) was added N,N-diisopropylethylamine(4.6 mL, 28.0 mmol, 2 equiv.) and the reaction solution was stirred at90° C. After 12 h the reaction solution was concentrated and purified bysilica gel column chromatography (10-50% ethyl acetate in petroleumether) to give4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(6.5 g, 11.7 mmol, 84% yield) as a brown oil. MS (ESI) m/z 554.4 [M+1]⁺;¹H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.4 Hz, 1H), 7.84 (d, J=2.0 Hz,1H), 7.74-7.71 (m, 1H), 4.60-4.58 (m, 1H), 3.84-3.82 (m, 2H), 3.71-3.61(m, 1H), 3.60-3.52 (m, 2H), 3.50-3.49 (m, 2H), 3.47-3.32 (m, 1H),2.22-2.20 (m, 2H), 2.19 (d, J=12.0 Hz, 2H), 1.88-1.87 (m, 6H), 1.85-1.84(m, 2H), 1.60 (s, 6H), 1.56-1.55 (m, 2H), 1.54-1.35 (m, 2H).

4-(3-(trans-4-(3-Hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(6.5 g, 11.7 mmol) in methanol (50 mL) was added 1 M aqueoushydrochloric acid (5.0 mL, 5 mmol) and the reaction solution was stirredat room temperature. After 2 h the reaction solution was diluted withsaturated aqueous sodium bicarbonate (30 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated to give4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(5.0 g, 10.7 mmol, 91% yield) as a brown oil. MS (ESI) m/z 470.2 [M+1]⁺.

4-(3-(trans-4-(3-Bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of give4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(5.0 g, 10.7 mmol, 1 equiv.) in dichloromethane (50 mL) andN,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3mmol, 4 equiv.) at 0° C. and the reaction solution was gradually warmedto room temperature. After 12 h the reaction solution was diluted withsaturated aqueous sodium bicarbonate (50 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated. The resultingcrude material was purified by silica gel column chromatography to give4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(5.0 g, 9.4 mmol, 88% yield) as a light yellow oil. MS (ESI) m/z 534.1[M+1]⁺; ¹H NMR (400 MHz, CDCl3) δ7.95 (d, J=8.4 Hz, 1H), 7.84 (d, J=2.0Hz, 1H), 7.74-7.71 (m, 1H), 3.71-3.61 (m, 1H), 3.60-3.53 (m, 2H), 3.52(t, J=6.4 Hz, 2H), 3.35-3.32 (m, 1H), 2.21 (d, J=12.0 Hz, 2H), 2.19-2.05(m, 2H), 1.83 (d, J=12.0 Hz, 2H), 1.65 (s, 2H), 1.60 (s, 6H), 1.35-1.32(m, 2H).

2-((2R,6S)-4-(3-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.150 g, 0.280 mmol, 1 equiv.) and2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.158 g, 0.420 mmol, 1.5 equiv.) in N,N-dimethylformamide (3 mL, 0.01M) was added N,N-diisopropylethylamine (0.15 mL, 0.85 mmol, 3 equiv.).The reaction mixture was stirred at 50° C. After 12 h the reactionsolution was diluted with water (50 mL) and the aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate, filteredand concentrated. The crude material was purified by standard methods toprovide2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.058 g, 0.069 mmol, 25% yield) as a yellow solid. MS(ESI) m/z 825.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.34(d, J=8.3 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H), 7.97 (dd, J=1.6, 8.3 Hz, 1H),7.12-6.94 (m, 2H), 6.87 (d, J=6.3 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H),4.37-4.24 (m, 4H), 3.96-3.61 (m, 4H), 3.51 (t, J=5.7 Hz, 2H), 3.26 (t,J=10.6 Hz, 2H), 3.12 (s, 2H), 2.84-2.56 (m, 4H), 2.09-1.84 (m, 6H), 1.72(d, J=10.6 Hz, 2H), 1.55 (s, 6H), 1.41-1.23 (m, 8H).

Example 13:2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

3-Chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile.A mixture of methyl 3-chloro-5-isothiocyanato- pyridine-2-carbonitrile(1.600 g, 8.18 mmol, 1 equiv.) and methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (2.320g, 9 mmol, 1.1 equiv.) in ethyl acetate (100 mL) was added triethylamine(2.28 mL, 16.36 mmol, 2 equiv.) and the reaction solution was stirred at90° C. After 6 h the reaction solution was concentrated and purified bysilica gel column chromatography (10-100% ethyl acetate in petroleumether) to give3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile(2.000 g, 4.75 mmol, 58% yield) as a yellow solid. MS (ESI) m/z 421.2[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.67-8.50 (m, 1H), 7.98-7.83 (m, 1H),3.80-3.48 (m, 4H), 2.75-2.52 (m, 2H), 1.93-1.60 (m, 6H), 1.51-1.28 (m,3H), 1.27-1.15 (m, 5H), 1.06-0.89 (m, 3H).

5-(3-(trans-4-(3-Bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile.To a solution of3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile(2.000 g, 4.75 mmol, 1 equiv.) in dichloromethane (5 mL, 0.1 M) andN,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.61 mL, 9.5mmol, 2 equiv.) at 0° C. The reaction solution was stirred at 25° C.After 16 h the pH of the reaction solution was adjusted to 8 by additionof saturated sodium carbonate. The aqueous phase was extracted withethyl acetate (100 mL×2). The combined organic layers were washed withbrine (25 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The crude material was purified by silica gel columnchromatography (50-100% ethyl acetate in petroleum ether) to give5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile(1.600 g, 3.31 mmol, 70% yield) as a red solid. MS (ESI) m/z 483.1[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.73-8.50 (m, 1H), 7.98-7.82 (m, 1H),3.78-3.65 (m, 1H), 3.37-3.29 (m, 2H), 2.77-2.49 (m, 2H), 1.93-1.80 (m,4H), 1.57-1.52 (m, 6H), 1.30 (br t, J=5.6 Hz, 3H), 1.08-0.97 (m, 2H).

2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile(0.100 g, 0.210 mmol, 1 equiv.) and2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (0.141 g, 0.310 mmol, 1.5 equiv.) in N,N-dimethylformamide(3 mL, 0.07 M) was added N,N-diisopropylethylamine (0.18 mL, 1.03 mmol,5 equiv.) in one portion under nitrogen. The mixture was stirred at 50°C. After 12 h the reaction mixture was diluted with water (80 mL) andextracted with ethyl acetate (4×30 mL). The combined organic layers werewashed with brine (50 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude material was purifiedby standard methods to give2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.073 g, 0.094 mmol, 45% yield) as a yellow solid. MS(ESI) m/z 776.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.24-11.28 (m, 1H),10.79 (s, 1H), 10.43 (br s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.53 (d, J=2.0Hz, 1H), 7.08-7.01 (m, 1H), 7.08-7.01 (m, 1H), 7.08-7.01 (m, 1H), 6.98(s, 1H), 6.85 (br d, J=7.9 Hz, 1H), 6.47 (br d, J=9.8 Hz, 1H), 4.27 (brdd, J=4.8, 11.3 Hz, 1H), 4.23-4.14 (m, 2H), 3.75 (br s, 6H), 3.21 (br s,2H), 3.05 (br s, 2H), 2.74 (ddd, J=5.3, 12.0, 17.4 Hz, 3H), 2.64-2.55(m, 1H), 2.09 (td, J=4.3, 8.7 Hz, 1H), 1.97-1.66 (m, 7H), 1.55 (s, 6H),1.34 (br s, 6H), 1.22 (br s, 3H), 1.09 (q, J=11.0 Hz, 2H).

Example 14:2-((2S,6R)-4-(3-(trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-Chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile.To a solution of methyl2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.31g, 5.1 mmol, 1 equiv.) and 2-chloro-4-isothiocyanatobenzonitrile (1.08g, 5.57 mmol, 1.1 equiv.) in ethyl acetate (25 mL) was addedN,N-diisopropylethylamine (2.51 mL, 15.18 mmol, 3 equiv.) and thereaction mixture was stirred at 80° C. After 18 h the reaction solutionwas concentrated and purified by column chromatography (15-50% ethylacetate in petroleum ether) to afford2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile(1.26 g, 3.01 mmol, 59% yield) as a brown oil. MS (ESI) m/z 420.1[M+1]⁺.

4-(3-(trans-4-(3-Bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile.To a solution of2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile(1.26 g, 3.01 mmol) in N,N-dimethylformamide (0.30 mL) anddichloromethane (3 mL) was added thionyl bromide (1.88 g, 9.03 mmol, 3equiv.) slowly at 0° C. After 12 h the reaction solution wasconcentrated under reduced pressure and purified by silica gel columnchromatography (15-30% ethyl acetate in petroleum ether) to give4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(1.21 g, 2.50 mmol, 83% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 7.79 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.4, 2.0Hz, 1H), 3.87 (m, 1H), 3.43 (t, J=6.8 Hz, 2H), 2.70 (s, 2H), 1.94-1.82(m, 6H), 1.59 (s, 6H), 1.39-1.36 (m, 3H), 1.12-1.03 (m, 2H).

2-((2S,6R)-4-(3-(trans-4-(3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile(0.100 g, 0.210 mmol) and2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (0.141 g, 0.310 mmol, 1.5 equiv.) in N,N-dimethylformamide(4 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.04 mmol, 5equiv.) in one portion under nitrogen. The mixture was stirred at 50° C.for 6 h. The reaction mixture was diluted with water (80 mL) andextracted with ethyl acetate (4×30 mL). The combined organic layers werewashed with brine (50 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude material was purifiedby standard methods to give2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.083 g, 0.106 mmol, 51% yield) as a yellow solid. MS(ESI) m/z 775.6 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.30-11.70 (m, 1H),10.80 (s, 1H), 10.59 (br s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.92 (d, J=1.8Hz, 1H), 7.61 (dd, J=1.9, 8.4 Hz, 1H), 7.09-7.02 (m, 1H), 7.00 (s, 1H),6.87 (br d, J=7.7 Hz, 1H), 6.48 (dd, J=1.5, 8.2 Hz, 1H), 4.28 (br dd,J=4.8, 11.3 Hz, 1H), 4.01-3.58 (m, 7H), 3.27 (br s, 2H), 3.05 (br s,2H), 2.84-2.65 (m, 3H), 2.64-2.55 (m, 1H), 2.09 (td, J=4.3, 8.7 Hz, 1H),1.97-1.88 (m, 1H), 1.87-1.67 (m, 6H), 1.53 (s, 6H), 1.37 (br d, J=4.4Hz, 6H), 1.22 (br s, 3H), 1.15-1.02 (m, 2H).

Example 15:2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

(2S,6R)-1-Benzyl-2,6-dimethylpiperidin-4-one. To a solution of3-oxopentanedioic acid (100.0 g, 684.5 mmol, 1 equiv.) in water (200 mL)was added acetaldehyde (150.8 g, 1368.9 mmol, 2 equiv.) at 20° C. Thereaction was stirred at 20° C. for 20 min and then cooled to 0° C. andphenylmethanamine (74.61 mL, 684.5 mmol, 1 equiv.) was added dropwise.The reaction solution was allowed to warm to room temperature andstirred for 48 h. The reaction solution was extracted with ethyl acetate3000 mL (1000 mL×3) and the combined organic layers were washed withbrine 500 mL. The organic layers were dried with anhydrous sodiumsulfate, filtrated and concentrated. The crude material was purified bysilica gel column chromatography to give(2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (27.70 g, 127.5 mmol, 19%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J=7.2 Hz,2H), 7.37-7.29 (m, 2H), 7.27-7.20 (m, 1H), 3.86 (s, 2H), 3.17-3.09 (qd,J=6.4, 13.2 Hz, 2H), 2.42-2.28 (m, 4H), 1.16 (d, J=6.4 Hz, 6H).

Ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate. To asolution of sodium hydride (8.283 g, 207.1 mmol, 1.5 equiv.) in THE (50mL) was added ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol,1.3 equiv.) in THE (100 mL) dropwise at 0° C. The mixture was stirred at0° C. for 30 min. (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g,138.1 mmol, 1 equiv.) in THF (200 mL) was added to above solutiondropwise and the reaction solution was warmed to room temperature. After12 h the reaction solution was neutralized by addition of ammoniumchloride saturated solution and poured into ice-water (200 mL). Theaqueous phase was extracted with ethyl acetate (3×500 mL). The combinedorganic layers were washed with brine (300 mL), dried with anhydroussodium sulfate, filtered and concentrated. The crude material waspurified by flash silica gel chromatography (2.0% ethyl acetate inpetroleum ether) (petroleum ether:ethyl acetate=3:1, Rf: 0.65) and thenre-purified by semi-preparative reverse phase HPLC (55-85%acetonitrile+0.05% ammonium hydroxide in water, over 20 min). Thecollected fraction was concentrated, and the aqueous phase was extractedwith ethyl acetate (3×500 mL). The combined organic layers were washedwith brine (300 mL), dried with anhydrous sodium sulfate, filtered andconcentrated to give ethyl2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (11.7 g,40.7 mmol, 30% yield) as a yellow oil. MS (ESI) m/z 288.2 [M+1]⁺; ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.35 (m, 2H), 7.30 (t, J=7.6 Hz, 2H), 7.26-7.16(m, 1H), 5.63 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 3.57 (dd,J=2.8, 14.0 Hz, 1H), 2.84-2.62 (m, 2H), 2.29-2.08 (m, 3H), 1.33-1.23 (m,3H), 1.14 (dd, J=6.4, 16.4 Hz, 6H).

tert-Butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate. Toa solution of ethyl2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (5.300 g,18.44 mmol, 1 equiv.) and di-tert-butyl dicarbonate (6.037 g, 27.66mmol, 1.5 equiv.) in THE (80 mL, 0.23 M) was added 10% Palladium oncarbon (1.500 g, 1.84 mmol, 10 mol %) under nitrogen. The reactionmixture was stirred at room temperature for 12 hours under hydrogen (50psi). The reaction mixture was filtered and concentrated to give aresidue which was purified by flash silica gel chromatography (1% ethylacetate in petroleum ether, petroleum ether:ethyl acetate=5:1) to givetert-butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate(2.630 g, 8.784 mmol, 48% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 4.26 (s, 1H), 4.21 (m, 1H), 4.17-4.10 (m, 2H), 2.26-2.18 (m,2H), 2.13-2.05 (m, 1H), 1.99-1.84 (m, 1H), 1.66-1.55 (m, 1H), 1.47 (s,9H), 1.36-1.29 (m, 1H), 1.29-1.25 (m, 3H), 1.24-1.19 (m, 6H), 1.15-1.02(m, 2H).

tert-Butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate. To asolution of lithium aluminumhydride (0.500 g, 13.18 mmol, 1.5 equiv.) inTHE (10 mL) was added a solution of tert-butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate(2.630 g, 8.780 mmol, 1 equiv.) in THE (40 mL) at 0° C. The reactionsolution was slowly warmed to room temperature over 1 h. The reactionsolution was quenched by addition water 0.5 mL, 15% sodium hydroxidesolution (1 mL) and water 1.5 mL. The slurry was stirred for 0.5 h,filtered and concentrated in vacuo. The crude material was diluted withwater 100 mL and extracted with ethyl acetate 100 mL×3. The combinedorganic layers were washed with brine 100 mL, dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bysilica gel column chromatography (20% ethyl acetate in petroleum ether)to provide tert-butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180g, 8.470 mmol, 96% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ4.40-4.25 (m, 1H), 4.24-4.07 (m, 1H), 3.77-3.65 (m, 2H), 2.12-2.03 (m,1H), 1.68-1.56 (m, 2H), 1.55-1.49 (m, 2H), 1.49-1.42 (m, 9H), 1.33-1.26(m, 1H), 1.25-1.17 (m, 6H), 1.05 (m, 1H).

tert-Butyl(2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate. To asolution of tert-butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180g, 8.470 mmol, 1 equiv.) and triphenylphosphine (3.332 g, 12.71 mmol,1.5 equiv.) in dichloromethane (40 mL, 0.21 M). To the reaction solutionwas added carbon tetrabromide (4.214 g, 12.71 mmol, 1.5 equiv.) at 0° C.The reaction mixture was allowed to slowly warm to room temperature.After 2 h the reaction solution was poured into saturated sodiumbicarbonate solution (100 mL) and the aqueous phase was extracted withdichloromethane (3×100 mL). The combined organic layers were washed withbrine (100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The crude material was purified by silica gelchromatography (1% ethyl acetate in petroleum ether) to providetert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate(2.160 g, 6.744 mmol, 80% yield) as a clear, colorless oil. ¹H NMR (400MHz, CDCl₃) δ 4.45-4.27 (m, 1H), 4.26-4.06 (m, 1H), 3.51-3.29 (m, 2H),2.18-1.96 (m, 2H), 1.89-1.75 (m, 2H), 1.73-1.53 (m, 2H), 1.48-1.39 (m,9H), 1.33-1.25 (m, 1H), 1.24-1.19 (m, 6H), 1.13-0.97 (m, 1H).

tert-Butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate.To a solution of trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22mmol, 2 equiv.) and tert-butyl(2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g,20.61 mmol, 1 equiv.) in xylene (120 mL, 0.17 M) was added potassiumhydroxide (5.318 g, 94.80 mmol, 4.6 equiv.) and tetrabutylammoniumbromide (1.328 g, 4.120 mmol, 0.2 equiv.). The reaction was stirred at30° C. After 24 h the reaction solution was diluted with water (200 mL)and extracted with ethyl acetate (3×250 mL). The combined organic layerswere washed with brine (150 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The crude material was purified by flashsilica gel column chromatography (2.5-3% ethyl acetate in petroleumether) to provide tert-butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(2.800 g, 5.236 mmol, 25% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.33 (m, 4H), 7.33-7.27 (m, 4H), 7.24-7.17 (m, 2H),4.36-4.23 (m, 2H), 4.22-4.15 (m, 1H), 3.62 (s, 4H), 3.48 (t, J=6.4 Hz,1H), 3.45-3.37 (m, 1H), 3.19-3.06 (m, 1H), 2.53 (m, 1H), 2.09-2.04 (m,3H), 2.01-1.86 (m, 3H), 1.63-1.59 (m, 1H), 1.57-1.51 (m, 2H), 1.47-1.46(m, 9H), 1.43-1.33 (m, 2H), 1.28-1.24 (m, 2H), 1.21 (s, 2H), 1.17 (d,J=7.0 Hz, 6H), 1.14-1.08 (m, 1H), 1.07-0.92 (m, 1H).

tert-Butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate.To a solution of tert-butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(2.800 g, 5.240 mmol, 1 equiv.) in methanol (60 mL) was added palladiumon carbon (2.000 g) under nitrogen. The reaction was stirred at roomtemperature for 12 hours under hydrogen (15 psi). The reaction mixturewas filtered and concentrated to give tert-butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(1.837 g, 5.180 mmol, 98% yield) yellow oil which was carried forwardwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 4.23-4.08 (m,2H), 4.08-3.93 (m, 1H), 3.50-3.40 (m, 2H), 3.40-3.33 (m, 1H), 3.18-3.04(m, 1H), 2.55-2.51 (m, 2H), 2.49 (br s, 1H), 2.05-1.83 (m, 4H),1.82-1.68 (m, 2H), 1.67-1.47 (m, 2H), 1.46-1.32 (m, 16H), 1.29-1.15 (m,2H), 1.15-1.07 (m, 9H), 1.07-0.87 (m, 3H).

tert-Butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate.To a solution of tert-butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(1.837 g, 5.180 mmol, 1 equiv.) in acetonitrile (10 mL, 0.5 M) was addedpotassium iodide (0.086 g, 0.520 mmol, 10 mol %), potassium carbonate(2.148 g, 15.54 mmol, 3 equiv.) and methyl 2-bromo-2-methylpropanoate(3.75 mL, 25.91 mmol, 5 equiv.). The reaction was stirred at 110° C.After 48 h the reaction solution was filtered and concentrated to givetert-butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(2.400 g, 5.279 mmol, crude) as a yellow oil which was carried forwardwithout further purification. MS (ESI) m/z 455.5 [M+1]⁺.

tert-Butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylateand tert-butyl(2R,4r,6S)-4-(2-(((1r,4R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate.To a solution of tert-butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(2.160 g, 4.750 mmol, 1 equiv.) and4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.084 g, 4.750 mmol, 1equiv.) in ethyl acetate (10 mL, 0.47 M) was addedN,N-diisoproplyethylamine (1.660 mL, 9.500 mmol, 2 equiv.). The reactionwas stirred at 90° C. After 12 h the reaction solution was diluted withwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine (50 mL), dried over anhydroussodium sulfate, filtered and concentrated. The crude material waspurified by flash silica gel column chromatography to afford the mixtureof diastereomers, which were separated by SFC (DAICEL CHIRAL PAK IG:250mm*30 mm·10 um, 20% methanol+0.1% NH₃·H2O) to give tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(1.060 g, 1.629 mmol, 34% yield) and tert-butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(0.360 g, 0.553 mmol, 12% yield). tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate:¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.0 Hz, 1H), 7.85 (d, J=2.0 Hz,1H), 7.72 (dd, J=2.0, 8.0 Hz, 1H), 4.38-4.22 (m, 2H), 3.72-3.59 (m, 1H),3.54 (t, J=6.4 Hz, 2H), 3.37-3.24 (m, 1H), 3.03-2.75 (m, 2H), 2.21 (brd, J=12.4 Hz, 2H), 2.03-1.90 (m, 1H), 1.89-1.77 (m, 2H), 1.61 (s, 6H),1.58 (m, 2H), 1.54-1.48 (m, 2H), 1.47 (s, 9H), 1.40-1.26 (m, 4H), 1.19(d, J=7.2 Hz, 6H). tert-Butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate:¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.4 Hz, 1H), 7.85 (d, J=2.0 Hz,1H), 7.72 (dd, J=2.0, 8.4 Hz, 1H), 4.28-4.10 (m, 2H), 3.76-3.58 (m, 1H),3.49 (t, J=6.0 Hz, 2H), 3.30 (m, 1H), 3.03-2.76 (m, 2H), 2.19 (br d,J=12.0 Hz, 2H), 2.12-1.98 (m, 2H), 1.89-1.76 (m, 2H), 1.61 (s, 6H), 1.52(br t, J=6.4 Hz, 2H), 1.47 (s, 9H), 1.40-1.25 (m, 3H), 1.22 (d, J=6.8Hz, 6H), 1.03 (m, 2H).

4-(3-(trans-4-(2-((2R,4s,6S)-2,6-Dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(1.060 g, 1.630 mmol, 1 equiv.) in dichloromethane (5 mL) was added 4 Mhydrochloric acid in 1,4-dioxane (20 mL, 80.00 mmol), and the reactionsolution was stirred at room temperature. After 2 h the reactionsolution was concentrated. The resulting yellow solid was taken up insaturated aqueous sodium bicarbonate (50 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate and concentrated to provide4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.920 g, 1.67 mmol, 99% yield) as a yellow solid which was carriedforward without further purification. MS (ESI) m/z 551.4 [M+1]+; ¹H NMR(400 MHz, CDCl₃) δ 7.95 (d, J=8.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.72(dd, J=2.0, 8.0 Hz, 1H), 3.74-3.59 (m, 1H), 3.51 (t, J=6.8 Hz, 2H), 3.31(m, 1H), 2.92 (m, 4H), 2.20 (br d, J=12.0 Hz, 2H), 2.02-1.92 (m, 1H),1.82 (br d, J=12.0 Hz, 2H), 1.70 (q, J=6.8 Hz, 2H), 1.64-1.56 (s, 6H),1.51 (br d, J=12.8 Hz, 2H), 1.40-1.27 (m, 4H), 1.09 (br d, J=6.0 Hz,6H).

2-Chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide.To a solution of3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (1.000 g, 3.870mmol, 1 equiv.) in dichloromethane (20 mL, 0.2 M) was addedtriethylamine (1.62 mL, 11.62 mmol, 3 equiv.) and 2-chloroacetylchloride (0.46 mL, 5.810 mmol, 1.5 equiv.) in one portion at 0° C. undernitrogen. After 2 h the reaction solution was diluted with water (150mL) and extracted with ethyl acetate (4×40 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The crude material was purified byflash silica gel column chromatography (0-100% Ethyl acetate indichloromethane) to provide2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide(0.750 g, 2.240 mmol, 58% yield) as a grey solid. MS (ESI) m/z 335.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 10.27 (s, 1H), 7.65(d, J=7.6 Hz, 1H), 7.18-7.08 (m, 2H), 4.39 (s, 2H), 4.21 (m, 1H), 4.06(s, 3H), 2.71-2.61 (m, 2H), 2.43-2.32 (m, 1H), 2.21-2.14 (m, 1H).

2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.100 g, 0.180 mmol, 1 equiv.) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.081 g,0.270 mmol, 1.5 equiv.) in N,N-dimethylformamide (2 mL, 0.1 M) was addedN,N-diisopropylethylamine (0.16 mL, 0.910 mmol, 5 equiv.) and sodiumiodide (0.027 g, 0.180 mmol, 1 equiv.). The reaction was stirred at 80°C. After 13 h the reaction solution was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated. The crude material was purified by standard methods togive2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.081 g, 0.099 mmol, 55% yield) as a yellow solid. MS(ESI) m/z 810.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 10.80(d, J=4.0 Hz, 1H), 10.60 (s, 1H), 10.17-9.89 (m, 1H), 9.04 (br s, 1H),8.33 (d, J=8.0 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.96 (dd, J=1.6, 8.0 Hz,1H), 7.12-6.95 (m, 2H), 6.86 (t, J=6.8 Hz, 1H), 6.56-6.39 (m, 1H), 4.27(dd, J=5.2, 11.6 Hz, 1H), 4.23-4.18 (m, 1H), 4.15 (br d, J=3.6 Hz, 1H),3.81-3.68 (m, 3H), 3.62-3.54 (m, 1H), 3.48 (br t, J=6.0 Hz, 2H), 3.22(m, 1H), 2.94-2.75 (m, 2H), 2.75-2.68 (m, 1H), 2.65-2.54 (m, 1H),2.15-2.01 (m, 3H), 2.01-1.84 (m, 3H), 1.79-1.60 (m, 6H), 1.54 (d, J=1.2Hz, 6H), 1.39-1.33 (m, 3H), 1.33-1.23 (m, 2H), 1.19 (d, J=6.4 Hz, 3H).

Example 16:2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

4-(3-(trans-4-(2-((2R,4r,6S)-2,6-Dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of tert-butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(0.360 g, 0.550 mmol, 1 equiv.) in dichloromethane (3 mL, 0.12 M) wasadded 4M hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol), and thereaction solution was stirred at 15° C. After 14 h the reaction solutionwas concentrated. The resulting solid was diluted with saturatedbicarbonate solution (20 mL) to pH 8-9 and the aqueous was extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (30 mL), dried over anhydrous sodium sulfate and concentratedto give4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.330 g, 0.56 mmol) as a yellow solid which was carried forward withoutfurther purification. MS (ESI) m/z 551.4 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃)δ 7.95 (d, J=8.4 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.72 (dd, J=2.0, 8.4Hz, 1H), 3.73-3.59 (m, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.30 (m, 1H),3.03-2.80 (m, 2H), 2.74 (m, 2H), 2.20 (br d, J=12.4 Hz, 2H), 1.82 (br d,J=11.6 Hz, 2H), 1.68 (br d, J=13.2 Hz, 2H), 1.61 (s, 6H), 1.54-1.48 (m,2H), 1.41-1.27 (m, 3H), 1.14 (br d, J=6.4 Hz, 6H), 0.92-0.76 (m, 2H).

2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.060 g, 0.110 mmol, 1 equiv.) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.048 g,0.160 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.11 M) wasadded N,N-diisopropylethylamine (0.09 mL, 0.540 mmol, 5 equiv.) andsodium iodide (0.016 g, 0.110 mmol, 1 equiv.). The reaction was stirredat 80° C. After 12 h the reaction solution was diluted with water (30mL) and extracted with ethyl acetate (3×30 mL). The combined organiclayers were washed with brine (50 mL) dried over anhydrous sodiumsulfate and concentrated. The crude material was purified by standardmethods to give2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.041 g, 0.0498 mmol, 46% yield). MS (ESI) m/z 810.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 10.67-10.31 (m, 1H),9.67-9.38 (m, 1H), 9.06 (br s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.18 (s,1H), 7.96 (dd, J=1.6, 8.4 Hz, 1H), 7.10-7.00 (m, 1H), 6.99-6.89 (m, 1H),6.83 (br d, J=8.0 Hz, 1H), 6.47 (m, 1H), 4.30-4.22 (m, 1H), 4.21-4.15(m, 1H), 4.09-4.02 (m, 1H), 3.90-3.79 (m, 2H), 3.53-3.42 (m, 4H),3.28-3.17 (m, 1H), 2.90-2.68 (m, 3H), 2.65-2.56 (m, 1H), 2.15-2.00 (m,3H), 1.99-1.79 (m, 3H), 1.78-1.64 (m, 3H), 1.58-1.50 (m, 6H), 1.49-1.36(m, 3H), 1.34 (br d, J=5.2 Hz, 3H), 1.30-1.22 (m, 1H), 1.20 (d, J=6.4Hz, 3H), 1.15-1.06 (m, 1H).

Example 17:2-((2R,6S)-4-(4-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

tert-Butyl(trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. To asolution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)aceticacid (2.000 g, 7.770 mmol, 1 equiv.) and N, O— dimethylhydroxylaminehydrochloride (0.830 g, 8.550 mmol, 1.1 equiv.) in N,N-dimethylformamide(20 mL, 0.38 M) was added N,N-diisopropylethylamine (6.94 mL, 38.86mmol) and HATU (4.430 g, 11.66 mmol, 5 equiv.) and the reaction solutionwas stirred at room temperature. After 12 h the reaction solution wasdiluted with water (100 mL) and extracted with ethyl acetate (2×60 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated. The resulting crude materialwas purified by silica gel column chromatography (0-30% ethyl acetate inpetroleum ether) to give tert-butyl(trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate(2.200 g, 7.323 mmol, 94% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 4.41 (s, 1H), 3.66 (s, 3H), 3.37 (s, 1H), 3.17 (s, 3H),2.31-2.29 (d, J=6.4 Hz, 2H), 2.04-1.97 (m, 2H), 1.85-1.79 (m, 3H), 1.43(s, 9H), 1.18-1.02 (m, 4H).

tert-Butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate. To a solution oftert-butyl(trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.2g, 7.320 mmol, 1 equiv.) in dichloromethane (10 mL) was added sodium asolution of 70% bis(2-methoxyethoxy)aluminum hydride in toluene (4.08mL, 14.65 mmol, 2 equiv.) at 0° C. After stirring for 2 h the reactionsolution was diluted with water (20 mL) and saturated aqueous ammoniumchloride (10 mL). The solution was extracted with dichloromethane (3×30mL), the combined organic layers were dried over anhydrous sodiumsulfate and concentrated. The resulting crude oil was purified by silicagel column chromatography (0-25% ethyl acetate in petroleum ether) toafford tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g,6.008 mmol, 82% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ9.65-9.64 (t, J=2.0 Hz, 1H), 6.69-6.64 (m, 1H), 3.19-3.13 (m, 1H),2.55-2.52 (m, 1H), 2.29-2.27 (m, 2H), 1.75-1.64 (m, 5H), 1.36 (s, 9H),1.17-1.08 (m, 2H), 1.06-0.83 (m, 2H).

Ethyl(E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate. To asolution of tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450g, 6.010 mmol, 1 equiv.) in toluene (10 mL, 0.6 M) was added ethyl2-(triphenylphosphoranylidene)acetate (2.300 g, 6.610 mmol, 1.1 equiv.)and the reaction mixture was stirred at 80° C. After 12 h the reactionsolution was concentrated and the resulting crude material was purifiedby silica gel column chromatography (0-20% ethyl acetate in hexanes) togive ethyl(E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate(0.890 g, 2.858 mmol, 48% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 6.95-6.88 (m, 1H), 5.82-5.78 (m, 1H), 4.36 (s, 1H), 4.24-4.14(m, 2H), 3.37 (s, 1H), 2.12-2.08 (m, 2H), 2.05-1.99 (m, 2H), 1.79-1.76(m, 2H), 1.46-1.36 (m, 10H), 1.31-1.27 (t, J=7.2 Hz, 3H), 1.13-0.99 (m,4H).

tert-Butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate. To a solutionof sodium borohydride (0.811 g, 21.43 mmol, 7.5 equiv.) in ethanol (16mL) and THE (16 mL) was added anhydrous lithium chloride (0.900 g, 21.43mmol, 7.5 equiv.) at 0° C. and the solution was stirred for 10 min. Tothe reaction solution was added a solution of ethyl(E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate(0.890. g, 2.860 mmol, 1 equiv.) in THE (8 mL) and the reaction solutionwas stirred at 15° C. After 12 h the reaction solution was quenched byslow addition of 1 M aqueous hydrochloric acid (10 mL) and the solutionwas extracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column chromatography (0-25% ethyl acetate in hexanes) togive tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g,2.763 mmol, 96% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.37(s, 1H), 3.66-3.62 (t, J=6.8 Hz, 2H), 3.36 (s, 1H), 2.00-1.98 (m, 2H),1.78-1.75 (m, 2H), 1.58-1.51 (m, 2H), 1.44 (s, 9H), 1.40-1.32 (m, 2H),1.28-1.14 (m, 4H), 1.08-0.94 (m, 4H).

4-(trans-4-Aminocyclohexyl)butan-1-ol. To a solution of tert-butyl(trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750. g, 2.760 mmol, 1equiv.) in dichloromethane (2 mL) was added 4 M hydrochloric acid in1,4-dioxane (4 mL, 16 mmol, 5.8 equiv.) and the reaction solution wasstirred at room temperature. After 12 h the reaction solution wasconcentrated to remove organic solvents and then diluted with saturatedsodium bicarbonate (30 mL) and extracted with ethyl acetate (2×30 mL).The combined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfated and concentrated to give4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.394 mmol, 87% yield)as a white solid which was carried forward without further purification.¹H NMR (400 MHz, CDCl₃) δ 3.62-3.59 (t, J=6.4 Hz, 2H), 2.61-2.54 (m,1H), 1.85-1.81 (m, 2H), 1.75-1.72 (m, 2H), 1.56-1.49 (m, 4H), 1.39-1.31(m, 2H), 1.25-1.12 (m, 3H), 1.10-1.00 (m, 2H), 0.97-0.87 (m, 2H).

Methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate.To a solution of methyl 2-bromo-2-methylpropanoate (1.733 g, 9.570 mmol,4 equiv.) and 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410. g, 2.390mmol, 1 equiv.) in acetonitrile (3 mL) was added potassium carbonate(0.993 g, 7.180 mmol, 3 equiv.) and sodium iodide (0.072 g, 0.480 mmol,0.2 equiv.) and the reaction solution was stirred at 80° C. After 12 hthe reaction solution was diluted with ethyl acetate, filtered andconcentrated to provide crude methyl2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000g, crude) as a brown oil. MS (ESI) m/z 272.3 [M+1]⁺.

4-(3-(trans-4-(4-Hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of methyl2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000.g, 2.320 mmol, 1 equiv.) and4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol,1.1 equiv.) in ethyl acetate (12 mL) was added N,N-diisopropylethylamine(1.15 mL, 6.960 mmol, 3 equiv.) and the reaction mixture was stirred forat 80° C. After 3 h the reaction solution was diluted with ethyl acetate(20 mL) and concentrated. The resulting crude oil was purified by silicagel column chromatography (0-35% ethyl acetate in petroleum ether) togive4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.360 g, 0.736 mmol, 32% yield) as a brown solid. MS (ESI) m/z 468.1[M+1]⁺.

4-(3-(trans-4-(4-Bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.To a solution of4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.360. g, 0.770 mmol, 1 equiv.) in dichloromethane (3 mL) was addedN,N-dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920mmol, 2.5 equiv.) and the reaction solution was stirred at 15° C. After12 h the reaction solution was concentrated and purified by silica gelcolumn chromatography (0-20% ethyl acetate in petroleum ether) to give4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.280 g, 0.517 mmol, 67% yield) as a brown solid. MS (ESI) m/z 530.0[M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.96-7.94 (d, J=8.4 Hz, 1H), 7.86-7.85(d, J=1.6 Hz, 1H), 7.75-7.72 (d, J=8.4, 1.6 Hz, 1H), 3.85 (s, 1H),3.45-3.41 (t, J=6.8 Hz, 2H), 2.69 (s, 2H), 1.95-1.92 (m, 2H), 1.88-1.83(m, 4H), 1.61 (s, 6H), 1.50-1.44 (m, 2H), 1.36-1.34 (m, 1H), 1.27-1.25(m, 2H), 1.11-1.01 (m, 2H).

2-((2R,6S)-4-(4-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.075 g, 0.140 mmol, 1 equiv.) and2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrobromide (0.084 g, 0.180 mmol, 1.3 equiv.) in N,N-dimethylformamide(2 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.710 mmol, 5equiv.) and the reaction solution was stirred at 50° C. After 12 h thereaction solution was diluted with water (20 mL) and extracted with 20:1dichloromethane/methanol (3×15 mL). the combined organic layers weredried over anhydrous sodium sulfate, concentrated and purified bystandard methods to give2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.034 g, 0.041 mmol, 29% yield) as a white solid. MS(ESI) m/z 823.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H),8.35-8.33 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.99-7.97 (d, J=8.0 Hz, 1H),7.06-7.02 (m, 1H), 6.98 (s, 1H), 6.84-6.82 (d, J=8.0 Hz, 1H), 6.46-6.44(m, 1H), 4.29-4.25 (m, 1H), 3.95-3.72 (m, 8H), 3.04 (m, 4H), 2.79-1.71(m, 2H), 2.62-2.58 (m, 1H), 2.12-2.08 (m, 1H), 1.95-1.89 (m, 1H),1.84-1.81 (m, 2H), 1.74-1.71 (m, 4H), 1.55 (s, 6H), 1.33-1.24 (m, 11H),1.13-1.07 (m, 2H).

Example 18:2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a 2 dram vial containing2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (200 mg, 0.33 mmol) and(S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (93.8 mg, 0.43 mmol,1.3 equiv.), added N,N-dimethylformamide (1.65 mL, 0.2 M) and stirreduntil all solids were dissolved. 1-Methylimidazole (0.26 mL, 3.29 mmol,10 equiv.) was added followed byN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate(V) (138.5 mg, 0.49 mmol, 1.5 equiv.) and thereaction solution was stirred at room temperature. After 20 min thereaction solution was diluted with DMSO to a total volume of 4 ml,filtered, and purified by standard methods to give2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(62 mg, 0.076 mmol, 23% yield). MS (ESI) m/z 809.4 [M+1]⁺; 1H NMR (400MHz, DMSO-d₆) δ=10.77 (s, 1H), 9.34 (s, 1H), 8.34 (d, J=8.3 Hz, 1H),8.20 (d, J=1.7 Hz, 1H), 7.98 (dd, J=1.7, 8.3 Hz, 1H), 7.08-6.95 (m, 2H),6.81-6.77 (m, 1H), 6.40 (dd, J=1.7, 8.1 Hz, 1H), 5.90 (d, J=7.9 Hz, 1H),4.35-4.22 (m, 1H), 3.90-3.72 (m, 1H), 3.20 (s, 2H), 2.82-2.54 (m, 8H),2.26-2.17 (m, 2H), 1.96-1.68 (m, 7H), 1.55 (s, 6H), 1.51-1.38 (m, 2H),1.30-1.03 (m, 5H), 0.98 (d, J=6.1 Hz, 6H)

Example 19:2-((R)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

tert-Butyl(R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To a 40 ml vial was added tert-butyl(R)-3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol),N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 equiv.), methylbromoacetate (1.09 mL, 11.8 mmol, 6 equiv.) and THE (20 mL, 0.1 M). Thereaction solution was stirred at room temperature. After 18 the solutionwas diluted with 100 ml ethyl acetate and 100 ml water. The organiclayer was removed, and the aqueous layer was extracted with 2×50 mlethyl acetate. Then combined organic layers were dried over magnesiumsulfate and concentrated. The crude material was purified by silica gelcolumn chromatography (1-50% ethyl acetate in hexanes) to providetert-butyl(R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.557 g, 1.71 mmol, 88% yield) as a yellow oil. MS (ESI) m/z 227[M-99]⁺.

Methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate. tert-Butyl(R)-3-(trifluoromethyl)piperazine-1-carboxylate (250 mg, 0.7 mmol), andtrifluoroacetic acid (0.58 mL, 7.6 mmol, 10 equiv.) were combined indichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screwcapped scintillation vial. After 1 h, the solution was concentratedmethyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (255 mg, 0.75mmol, 98% yield) as a yellow oil that was carried forward withoutfurther purification. MS (ESI) m/z 227 [M+1]⁺.

Methyl2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate.To a 1-dram vial containing4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.5 g, 0.96 mmol, 1 equiv.), methyl(S)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (0.33 g, 0.96 mmol, 1equiv.) and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.) was addedacetonitrile (5 mL) followed by N,N-diisopropylethylamine (0.8 mL, 4.82mmol, 5 equiv.). The reaction vial was heated with stirring to 60° C.After 16 h the reaction solution was diluted with ethyl acetate (100mL), washed with saturated aqueous sodium chloride (100 mL), dried overanhydrous sodium sulfate and concentrated. The crude material waspurified by silica gel column chromatography (0-100% ethyl acetate inhexane) to afford methyl2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(0.6 g, 0.89 mmol, 91% yield). MS (ESI) m/z 664.2 [M+1]⁺.

2-((R)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid. To a chilled solution of methyl2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(0.6 g, 0.9 mmol, 1 equiv.) in a mixture oftetrahydrofuran/methanol/water (3:1:1, 5 mL), lithium hydroxidemonohydrate (0.58 g, 1.3 mmol, 1.5 equiv.) was added in one portion at0° C. The resulting solution was stirred at room temperature. After 3 hthe reaction solution was diluted with water (20 mL) and extracted with10% methanol in dichloromethane (4×50 mL). The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated to give the2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (0.33 g, 0.46 mmol, 51% yield), which was carried forward withoutfurther purification. MS (ESI) m/z 650.2 [M+1]⁺.

2-((R)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a 2 dram vial containing2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (0.12 g, 0.19 mmol, 1 equiv.) and3-((3-aminophenyl)amino)piperidine-2,6-dione (0.05 g, 0.22 mmol, 1.2equiv.) was added acetonitrile (1.5 mL) and N,N-dimethylformamide (1.5mL) and the reaction solution was stirred until all solids weredissolved. To the reaction solution was added 1-methylimidazole (0.07mL, 0.84 mmol, 5 equiv.) followed byN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (0.12 g, 0.41 mmol, 2.2 equiv.) and the reactionsolution was stirred at room temperature. After 1 h the reactionsolution was diluted with dimethylsulfoxide to a total volume of 3 ml,filtered, and purified by standard methods to give2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.09 g, 0.11 mmol, 58% yield). MS (ESI) m/z 851.2 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 9.68 (s, 1H), 8.27 (d, J=8.2Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.90 (dd, J=1.6, 8.2 Hz, 1H), 7.04-6.89(m, 2H), 6.77 (br d, J=6.5 Hz, 1H), 6.36 (br d, J=8.2 Hz, 1H), 4.20 (brdd, J=4.5, 10.9 Hz, 2H), 3.87-3.44 (m, 8H), 3.30 (br d, J=11.2 Hz, 4H),3.06 (br d, J=9.7 Hz, 3H), 2.89-2.51 (m, 4H), 2.10-1.97 (m, 3H), 1.84(dq, J=4.7, 12.1 Hz, 1H), 1.72-1.61 (m, 2H), 1.48 (s, 6H), 1.38-1.19 (m,2H).

Example 20:2-((R)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

Methyl2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate.To a 1-dram vial containing5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(375 mg, 0.72 mmol, 1 equiv.) and methyl(R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate trifluoroacetate (491.3mg, 1.44 mmol, 2 equiv.) was added N,N-dimethylformamide (3.6101 mL, 0.2M) and N,N-diisopropylethylamine (0.75 mL, 4.33 mmol, 6 equiv.). Thereaction solution was heated to 55° C. with stirring. After 16 h thereaction solution was diluted with 75 ml ethyl acetate, washed withsaturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). Theorganic layer was separated and dried over magnesium sulfate to give ayellowish oil. The crude material was purified by reverse-phase HPLC toprovide the title compound as the formate salt. The material taken up inethyl acetate and washed with saturated sodium bicarbonate. The organiclayer was dried over magnesium sulfate and concentrated to methyl2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(310 mg, 0.4664 mmol, 65% yield). MS (ESI) m/z 655.2 [M+1]⁺; ¹H NMR (400MHz, CHLOROFORM-d) δ 1.62 (s, 6H) 1.81 (br d, J=11.86 Hz, 2H) 2.20 (brd, J=10.76 Hz, 2H) 2.48 (ddd, J=11.03, 7.92, 3.30 Hz, 1H) 2.52-2.69 (m,4H) 2.81-2.94 (m, 4H) 2.94-3.03 (m, 1H) 3.27-3.38 (m, 1H) 3.46 (dd,J=17.85, 0.98 Hz, 1H) 3.56-3.70 (m, 5H) 3.71 (s, 3H) 8.23 (d, J=2.20 Hz,1H) 8.97 (d, J=2.20 Hz, 1H)

2-((R)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate.To a 2-dram vial containing methyl2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(200 mg, 0.30 mmol) added 1,4-dioxane (1 mL, 0.3 M) followed by a 1 Msolution of lithium hydroxide in water (0.36 mL, 0.36 mmol, 1.2 equiv.).The reaction solution was stirred at room temperature for 2 h, at thispoint these is no remaining starting material by LCMS. The reactionsolution was concentrated and the resulting material was dried byazeotropic removal with dioxane to afford2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(193 mg, 0.29 mmol, 98% yield) as a glassy yellow oil. The material wascarried forward without further purification. MS (ESI) m/z 651.2 [M+1]⁺.

2-((R)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a 1-dram vial containingN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate(V) (112.2 mg, 0.40 mmol, 2 equiv.) added a solutionof2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate(131.31 mg, 0.20 mmol, 1 equiv.) in N,N-dimethylformamide (1.0 mL, 0.2M) followed by 3-((3-aminophenyl)amino)piperidine-2,6-dione (66 mg, 0.30mmol, 1.5 equiv) and 1-methylimidazole (98.5 mg, 1.2 mmol, 6 equiv.).The reaction solution was stirred at room temperature for 2 h. Thereaction solution was diluted to a total volume of 2 ml with DMSO,filtered, and purified by standard methods to give2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (98 mg, 0.11 mmol, 53% yield) as an off white solid. MS(ESI) m/z 852.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ=10.80 (s, 1H), 10.72(br s, 1H), 9.72 (s, 1H), 9.15 (d, J=1.8 Hz, 1H), 8.75 (d, J=2.0 Hz,1H), 7.06-6.94 (m, 2H), 6.89-6.77 (m, 1H), 6.42 (br d, J=7.6 Hz, 1H),4.16-4.14 (m, 1H), 3.86 (br s, 4H), 3.62 (br s, 5H), 3.45-3.29 (m, 4H),3.21-3.03 (m, 3H), 2.95-2.66 (m, 3H), 2.19-2.07 (m, 3H), 1.98-1.84 (m,1H), 1.80-1.69 (m, 2H), 1.58 (s, 6H), 1.44-1.29 (m, 2H).

Example 21:2-((2S,4r,6R)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

5-(3-((trans)4-(2-((2S,4r,6R)-2,6-Dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of (2S,4r,6R)-tert-butyl4-(2-(((1r,4R)-4-(3-(6-cyano-5-(1,1-difluoroethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(2.000 g, 3.070 mmol) in DCM (5 mL) was added 45 M HCl in dioxane (30.0mL, 120 mmol). The reaction mixture was stirred at 15° C. for 3 hoursand the reaction was concentrated to give a residue. The residue wasdiluted with saturated aqueous sodium bicarbonate (50 mL) to pH 8-9 andthe aqueous layer was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated to provide5-(3-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(1.940 g, 3.517 mmol) as yellow solid which was carried forward withoutfurther purification. MS (ESI) m/z: 552.4 [M+1]⁺; ¹H NMR (400 MHz,CDCl³) δ 8.97 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 3.79-3.58 (m,1H), 3.56-3.46 (m, 2H), 3.30 (m, 1H), 3.03-2.83 (m, 2H), 2.78 (m, 2H),2.26-2.15 (m, 2H), 1.89-1.75 (m, 2H), 1.69 (br d, J=13.2 Hz, 2H), 1.62(s, 6H), 1.52 (q, J=6.8 Hz, 2H), 1.41-1.29 (m, 2H), 1.27-1.11 (m, 6H),0.88 (q, J=11.2 Hz, 2H).

2-((2S,4r,6R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of5-(3-((1R,4r)-4-(2-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.120 g, 0.220 mmol), and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.096 g,0.330 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol). Thereaction mixture was stirred at 80° C. for 12 hours, and then dilutedwith water (30 mL). The aqueous layer was extracted with ethyl acetate(3×30 mL), and the combined organic layers were washed with brine (50mL), dried over sodium sulfate and concentrated. The resulting residuewas purified by standard methods to provide2-((2S,4r,6R)-4-(2-(((1r,4R)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.075 g, 0.090 mmol, 41.2% yield) as yellow solid. MS (ESI) m/z: 811.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.80 (s, 1H),10.68-10.53 (m, 1H), 10.24-9.95 (m, 1H), 9.14 (d, J=2.0 Hz, 1H), 9.07(br s, 1H), 8.74 (d, J=1.6 Hz, 1H), 7.05 (m, 1H), 6.99 (br d, J=7.2 Hz,1H), 6.87 (br d, J=8.0 Hz, 1H), 6.57-6.36 (m, 1H), 4.26 (m, 1H), 4.21(br s, 1H), 4.12 (br d, J=3.6 Hz, 1H), 3.92-3.77 (m, 1H), 3.70-3.56 (m,1H), 3.56-3.39 (m, 3H), 3.23 (m, 1H), 2.92-2.68 (m, 3H), 2.64-2.55 (m,1H), 2.14-2.00 (m, 3H), 1.98-1.82 (m, 2H), 1.82-1.63 (m, 4H), 1.56 (d,J=1.6 Hz, 6H), 1.50 (m, 1H), 1.47-1.38 (m, 2H), 1.38-1.22 (m, 5H), 1.20(d, J=6.4 Hz, 3H), 1.17-1.07 (m, 1H).

Example 22:2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-Dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile.To a solution of (2S,4s,6R)-tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate(0.885 g, 1.360 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (20 mL,80 mmol) and the reaction solution was stirred at 15° C. After 12 h thesolution was concentrated, and the resulting residue was diluted withaqueous sodium bicarbonate solution. The Aqueous solution was extractedwith ethyl acetate (3×100 mL) and the combined organic layers werewashed with brine (50 mL), dried over sodium sulfate and concentrated toprovide5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-Dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.750 g, 1.360 mmol) was obtained as yellow solid which was carriedforward without further purification. MS (ESI) m/z: 552.5 [M+1]⁺; ¹H NMR(400 MHz, CDCl³) δ 8.97 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H),3.78-3.59 (m, 1H), 3.51 (t, J=6.8 Hz, 2H), 3.31 (m, 1H), 3.02-2.72 (m,4H), 2.21 (br d, J=12.4 Hz, 2H), 2.01-1.95 (m, 1H), 1.82 (br d, J=12.0Hz, 2H), 1.70 (q, J=6.8 Hz, 2H), 1.63 (s, 6H), 1.52 (br d, J=13.6 Hz,2H), 1.41-1.26 (m, 4H), 1.10 (d, J=6.4 Hz, 6H).

2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of5-(3-((trans)-4-(2-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.120 g, 0.220 mmol) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.095 g,0.330 mmol) in DMF (0.500 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.19 mL, 1.090 mmol) and sodiumiodide (0.033 g, 0.220 mmol). The reaction mixture was stirred at 80° C.for 12 hours. The reaction mixture was diluted with water (30 mL) andthe aqueous layer was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (50 mL), dried oversodium sulfate and concentrated. The resulting residue was purified bystandard methods to provide2-((2S,4s,6R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.064 g, 0.079 mmol, 36.1% yield) as a yellow solid. MS (ESI) m/z:811.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.80 (br d,J=3.6 Hz, 1H), 10.62 (s, 1H), 10.27-9.86 (m, 1H), 9.14 (d, J=1.2 Hz,1H), 9.08-8.97 (m, 1H), 8.74 (d, J=1.6 Hz, 1H), 7.17-6.94 (m, 2H),6.93-6.73 (t, J=6.8 Hz, 1H), 6.57-6.37 (m, 1H), 4.30-4.25 (m, 1H), 4.21(br s, 1H), 4.17 (m, 1H), 3.87-3.78 (m, 2H), 3.59 (br s, 1H), 3.48 (brt, J=6.0 Hz, 2H), 3.30-3.11 (m, 1H), 2.93-2.67 (m, 3H), 2.63-2.57 (m,1H), 2.16-1.86 (m, 6H), 1.82-1.59 (m, 7H), 1.56 (d, J=1.2 Hz, 6H), 1.35(br s, 3H), 1.33-1.25 (m, 2H), 1.19 (br d, J=6.0 Hz, 3H).

Example 23:2-((R)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide

2-((R)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide.To a solution of4-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.150 g, 0.290 mmol) andN-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.150 g, 0.350 mmol) in DMF (3 mL) was added potassium iodide (0.048 g,0.290 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.870 mmol).The reaction mixture was stirred at 50° C. for 12 h. The reactionsolution was diluted with water (30 mL) and the aqueous phase wasextracted with ethyl acetate (2×30 mL). The combined organic phase waswashed with brine (20 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting residue was purified by standard methods togive2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide(0.062 g, 0.070 mmol, 24.2% yield) as a yellow solid. MS (ESI) m/z:869.6 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.93 (s, 1H),8.34 (d, J=8.4 Hz, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.97 (dd, J=1.6, 8.3 Hz,1H), 6.80-6.59 (m, 2H), 6.22 (d, J=12.1 Hz, 1H), 4.45-4.31 (m, 1H),4.30-4.24 (m, 1H), 3.87 (s, 2H), 3.82-3.56 (m, 8H), 3.25-3.03 (m, 4H),2.92-2.61 (m, 4H), 2.10-1.87 (m, 1H), 1.75-1.67 (m, 2H), 1.54 (s, 6H),1.39-1.29 (m, 2H).

Example 24:2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide

(3R)-tert-butyl4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To solution of(S)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (0.263 g, 0.840 mmol) and HATU (0.641 g, 1.69 mmol) in DMF (5 mL)was added N-ethyl-N-isopropylpropan-2-amine (0.44 mL, 2.53 mmol) and3-((3-amino-5-fluorophenyl)amino)piperidine-2,6-dione (0.200 g, 0.840mmol). The reaction mixture was stirred at 50° C. for 12 h. The mixturewas diluted with water (30 mL) and the aqueous phase was extracted withethyl acetate (2×30 mL). The combined organic layers were washed withbrine (2×20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica gel column chromatography (0-4% methanol indichloromethane) to give (3S)-tert-butyl4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.340 g, 0.640 mmol, 75.9% yield) as a brown oil. MS (ESI) m/z: 554.4[M+23]⁺.

N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide.To solution of (3S)-tert-butyl4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.340 g, 0.640 mmol) in DCM (5 mL) was added 33% hydrogen bromide inacetic acid (0.5 mL) and the reaction mixture was stirred at 25° C. for12 h. The mixture was concentrated under reduced pressure to giveN-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.270 g, 0.626 mmol, 97.8% yield) as a brown oil and used into the nextstep without further purification. MS (ESI) m/z 432.3 [M+1]⁺.

2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide.To a solution of5-(3-((1R,4R)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.100 g, 0.190 mmol) andN-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)-2-((S)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.100 g, 0.230 mmol) in DMF (3 mL) was added potassium iodide (0.032 g,0.190 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.580 mmol).The reaction mixture was stirred at 50° C. for 12 h, diluted with DMSOand purified by standard methods to give2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide(0.062 g, 0.071 mmol, 36.8% yield) as a green solid. MS (ESI) m/z 870.6[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 11.53-10.98 (m, 1H), 10.79 (s, 1H),9.94 (br s, 1H), 9.14 (d, J=1.9 Hz, 1H), 8.74 (d, J=1.9 Hz, 1H),6.85-6.57 (m, 2H), 6.22 (d, J=11.9 Hz, 1H), 4.40 (s, 1H), 4.28 (dd,J=4.7, 11.2 Hz, 3H), 3.74-3.50 (m, 6H), 3.47-3.28 (m, 4H), 3.20-3.11 (m,2H), 2.94-2.79 (m, 2H), 2.73 (ddd, J=4.7, 12.2, 17.0 Hz, 1H), 2.63-2.54(m, 1H), 2.14-2.03 (m, 3H), 1.94-1.84 (m, 1H), 1.72 (br d, J=11.3 Hz,2H), 1.56 (s, 6H), 1.41-1.29 (m, 2H).

Example 25:2-((R)-4-(3-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((R)-4-(3-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution ofN-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamidehydrobromide (0.180 g, 0.360 mmol) and5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.188 g, 0.360 mmol) in DMF (1 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.820 mmol). The reactionmixture was stirred at 50° C. for 12 hours. The reaction solution wasdiluted with water (30 mL), extracted with ethyl acetate (3×30 mL), andthe combined organic layers were dried over sodium sulfate andconcentrated. The resulting crude material was purified by standardmethods to give2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.078 g, 0.090 mmol, 25% yield) as a yellow solid. MS(ESI) m/z 850.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 11.27-11.00 (m, 1H),10.79 (s, 1H), 9.80-9.59 (m, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0Hz, 1H), 7.09-6.95 (m, 2H), 6.90-6.75 (m, 1H), 6.43 (br d, J=8.0 Hz,1H), 4.38 (br s, 1H), 4.27 (br dd, J=4.8, 11.2 Hz, 1H), 3.67-3.55 (m,4H), 3.54-3.43 (m, 2H), 3.22-2.94 (m, 5H), 2.90-2.68 (m, 3H), 2.64-2.54(m, 1H), 2.16-2.03 (m, 1H), 1.96-1.81 (m, 3H), 1.81-1.66 (m, 4H), 1.57(s, 6H), 1.33-1.15 (m, 3H), 1.15-0.99 (m, 2H).

Example 26:N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide.To a solution ofN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.172 g, 0.390 mmol) in DMF (1 mL) was added5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.100 g, 0.190 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.026 g,0.960 mmol). Then the reaction mixture was stirred at 50° C. for 12 h.The reaction solution was diluted with DMSO and purified by standardmethods to giveN-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.072 g, 0.075 mmol, 39% yield) as yellow solid. MS (ESI) m/z 886.0[M+1]⁺; ¹HNMR (400 MHz, DMSO-d6) δ 10.83-10.77 (m, 1H), 9.97-9.66 (m,1H), 9.15 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.6 Hz, 1H), 7.02-6.74 (m, 2H),6.46 (s, 1H), 4.43-4.25 (m, 2H), 3.87 (s, 3H), 3.75-3.57 (m, 5H),3.36-3.32 (m, 2H), 3.27-2.99 (m, 4H), 2.92-2.61 (m, 4H), 2.16-2.02 (m,3H), 1.98-1.84 (m, 1H), 1.78-1.68 (m, 2H), 1.57 (s, 6H), 1.44-1.31 (m,2H).

Example 27:N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide

(3R)-tert-Butyl4-(2-((3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To a solution of 3-(3-amino-5-chloro-anilino)piperidine-2,6-dione (0.162g, 0.640 mmol) and(R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (0.200 g, 0.640 mmol) in pyridine (1 mL) was added EDCI (0.246 g,1.28 mmol) and the reaction solution was heated to 50° C. After 12 h thereaction solution was concentrated, diluted with water (40 mL) andextracted with ethyl acetate (3×40 mL). the combined organic layers weredried over anhydrous sodium sulfate and purified by standard methods togive (3R)-tert-butyl4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.250 g, 0.456 mmol, 71.2% yield) as a yellow solid. MS (ESI) m/z 548.1[M+1]⁺.

(3R)-tert-Butyl4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To a solution of (3R)-tert-butyl4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.250 g, 0.460 mmol) in 33% HBr in AcOH (0.5 mL, 0.460 mmol) wasstirred at 25° C. After 12 h the reaction solution was concentrated togive (3R)-tert-butyl4-(2-((3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.200 g, 0.447 mmol, 97.9% yield) as a green solid, which was carriedforward without further purification. MS (ESI) m/z 448.1 [M+1]⁺.

N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide.To a solution of4-[3-[4-(2-bromoethoxy)cyclohexyl]-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile(0.100 g, 0.190 mmol) in DMF (1 mL) was addedN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.172 g, 0.390 mmol), N-ethyl-N-isopropylpropan-2-amine (0.124 g, 0.960mmol) and the reaction solution was heated to 50° C. After 12 h thereaction solution was diluted with DMSO and purified by standard methodsto provideN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.083 g, 0.089 mmol, 46.0% yield) as a yellow solid. MS (ESI) m/z 885.0[M+1]⁺; ¹HNMR (400 MHz, DMSO-d6) δ 10.80 (s, 2H), 10.01-9.67 (m, 1H),8.34 (d, J=8.4 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.01-7.93 (m, 1H),7.05-6.72 (m, 2H), 6.46 (s, 1H), 4.47-4.23 (m, 2H), 3.92-3.79 (m, 3H),3.77-3.47 (m, 7H), 3.20-3.06 (m, 3H, 3.00-2.76 (m, 3H), 2.75-2.66 (m,1H), 2.64-2.53 (m, 1H), 2.14-2.02 (m, 3H), 1.98-1.83 (m, 1H), 1.74 (dd,J=12 Hz, 2H), 1.55 (s, 6H), 1.45-1.30 (m, 2H).

Example 28:2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

tert-Butyl(3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To a mixture of 3-(3-aminoanilino)piperidine-2,6-dione hydrochloride(0.737 g, 2.88 mmol) and2-[(2R)-4-tert-butoxycarbonyl-2-(trifluoromethyl)piperazin-1-yl]aceticacid (0.600 g, 1.92 mmol) in pyridine (2 mL) was addedN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.737 g,3.84 mmol) and the reaction solution was heated to 50° C. After 16 h thereaction solution was diluted with water (25 mL), extracted with ethylacetate (100 mL), and the organic layer was dried over sodium sulfateand concentrated. The resulting crude residue was purified by standardmethods to give tert-butyl(3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.450 g, 0.88 mmol, 46% yield) as a yellow oil. MS (ESI) m/z 514.2[M+1]⁺.

N-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamidehydrobromide. To a solution of tert-butyl(3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.450 g, 0.88 mmol) in dichloromethane (10 mL) was added 30% hydrogenbromide in acetic acid (0.60 mL, 8.76 mmol) and the reaction solutionwas stirred at room temperature. After 16 h the reaction solution wasconcentrated to provide crudeN-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamidehydrobromide (0.500 g, 1.01 mmol), which was carried forward withoutfurther purification. MS (ESI) m/z 414.1 [M+1]⁺.

2-((R)-4-(3-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a mixture of5-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.129 g, 0.24 mmol) andN-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamidehydrobromide (0.120 g, 0.24 mmol) in N,N-dimethylformamide (2 mL) wasadded diisopropylethylamine (0.06 mL, 0.73 mmol) and the reactionsolution was stirred at 50° C. After 16 h the reaction solution wasdiluted with water (50 mL) and extracted with ethyl acetate (2×80 mL).the combined organic layers were dried over anhydrous sodium sulfate andconcentrated. The resulting crude residue was purified by standardmethods to provide2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.045 g, 0.05 mmol, 20.7% yield). MS (ESI) m/z 866.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d6) δ 11.08 (br d, J=5.6 Hz, 1H), 10.80 (s, 1H),9.82-9.56 (m, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.98 (dd,J=1.6, 8.0 Hz, 1H), 7.01 (br t, J=8.0 Hz, 2H), 6.92-6.72 (m, 1H), 6.43(br d, J=8.0 Hz, 1H), 4.44-4.23 (m, 2H), 3.91-3.76 (m, 1H), 3.71-3.41(m, 5H), 3.40-2.91 (m, 6H), 2.85-2.67 (m, 3H), 2.64-2.56 (m, 1H),2.15-2.04 (m, 1H), 1.92-1.70 (m, 7H), 1.55 (s, 6H), 1.42-0.91 (m, 6H).

Example 29:2-((R)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((R)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a mixture of4-(3-((1r,4r)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.126 g, 0.24 mmol) and tert-butyl(3R)-4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylatehydrobromide (0.120 g, 0.24 mmol) in N,N-dimethylformamide (2 mL) wasadded diisopropylethylamine (0.06 mL, 0.73 mmol) and the reactionsolution was stirred at 50° C. After 16 h the reaction solution wasdiluted with water (50 mL) and extracted with ethyl acetate (2×80 mL).the combined organic layers were dried over, sodium sulfate andconcentrated. The resulting crude material was purified by standardmethods to provide2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.057 g, 0.06 mmol, 26.7% yield) as a yellow solid. MS (ESI) m/z 849.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 11.14-10.94 (m, 1H), 10.79 (br s,1H), 9.82-9.50 (m, 1H), 9.14 (br s, 1H), 8.74 (br s, 1H), 7.01 (br s,2H), 6.90-6.73 (m, 1H), 6.50-6.34 (m, 1H), 4.30-4.24 (m, 2H), 3.66-3.45(m, 7H), 3.29-3.00 (m, 7H), 2.91-2.64 (m, 5H), 2.15-1.83 (m, 7H),1.77-1.68 (m, 2H), 1.57 (br d, J=3.2 Hz, 6H), 1.42-1.24 (m, 2H).

Example 30:2-((R)-4-(3-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((R)-4-(3-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.A solution of4-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.258 g, 0.480 mmol) andN-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.200 g, 0.480 mmol) in DMF (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.25 mL, 1.45 mmol) and potassiumiodide (80.31 mg, 0.4800 mmol) and the reaction solution was stirred at50° C. After 12 h the reaction solution was diluted with water (50 mL)and extracted with ethyl acetate (2×30 mL). The organic layers werecombined, dried over sodium sulfate, concentrated, and purified bystandard methods to provide2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.059 g, 0.068 mmol, 14.1% yield) as a yellow solid. MS(ESI) m/z 865.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.71(s, 1H), 8.33 (d, J=8.3 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.96 (dd,J=1.6, 8.2 Hz, 1H), 7.05-6.94 (m, 2H), 6.87-6.74 (m, 1H), 6.41 (br d,J=8.5 Hz, 1H), 4.43-4.27 (m, 1H), 4.27-4.22 (m, 1H), 3.91-3.74 (m, 2H),3.66 (s, 4H), 3.32-3.00 (m, 8H), 2.90-2.61 (m, 4H), 2.07 (dd, J=2.5, 6.0Hz, 3H), 1.99-1.82 (m, 3H), 1.71 (d, J=11.1 Hz, 2H), 1.54 (s, 6H),1.36-1.25 (m, 2H).

Example 31:N-(3-Cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide

(3R)-tert-Butyl4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.To solution of(R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (0.128 g, 0.410 mmol) and HATU (311.34 mg, 0.8200 mmol) in DMF (3mL) was added N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23 mmol) and3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (100. mg, 0.4100mmol). The reaction mixture was stirred at 50° C. for 12 h. The mixturewas diluted with water (30 mL) and the aqueous phase was extracted withethyl acetate (2×30 mL). The combined organic layers was washed withbrine (2×20 mL)), dried over anhydrous sodium sulfate and concentrated.The resulting crude material was purified by standard methods to provide(3R)-tert-butyl4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(140 mg, 0.2600 mmol, 63% yield) as a brown oil. MS (ESI) m/z 539.3[M+1]⁺.

N-(3-Cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide.To solution of (3R)-tert-butyl4-(2-((3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate(0.470 g, 0.870 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (1.0 mL, 12.89 mmol) and the reaction mixture wasstirred at 25° C. After 12 h the reaction solution was concentrated toprovide crudeN-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.380 g, 0.867 mmol, 99% yield) as a yellow solid that was carriedforward without further purification. MS (ESI) m/z 439.2 [M+1]⁺.

N-(3-Cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide.A solution5-(3-((1r,4r)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.213 g, 0.410 mmol) andN-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.180 g, 0.410 mmol) in DMF (3 mL) was added potassium iodide (0.068 g,0.410 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23 mmol),and stirred at 50° C. After 12 h the reaction solution was diluted withwater (30 mL) and extracted with ethyl acetate (2×20 mL). the combinedorganic layers were dried over anhydrous sodium sulfate, concentrated,and purified by standard methods to provideN-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.059 g, 0.0675 mmol, 16% yield) as a green solid. MS (ESI) m/z 877.5[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.76 (s, 1H), 9.14(d, J=1.8 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.22 (s, 2H), 6.77 (s, 1H),6.50 (d, J=8.0 Hz, 1H), 4.43-4.36 (m, 1H), 3.94-3.81 (m, 1H), 3.71-3.57(m, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.40 (d, J=16.1 Hz, 2H), 3.32-3.22 (m,8H), 2.90-2.75 (m, 4H), 2.11-2.03 (m, 3H), 1.96-1.86 (m, 1H), 1.71 (d,J=11.4 Hz, 2H), 1.56 (s, 6H), 1.36-1.24 (m, 2H).

Example 32:2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2R,4r,6S)-4-(3-((1r,4R)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)aceticacid (0.150 g, 0.240 mmol) and3-((3-aminophenyl)amino)piperidine-2,6-dione (0.079 g, 0.360 mmol) inpyridine (2 mL) was added EDCI (0.086 g, 0.480 mmol) and the reactionsolution was stirred at 50° C. After 12 h the reaction solution wasdiluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).the combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The resulting crude material waspurified by standard methods to provide2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.068 g, 0.080 mmol, 33.4% yield) as a grey solid. MS(ESI) m/z 824.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H),10.73-10.62 (m, 1H), 10.50 (s, 1H), 9.14 (br s, 1H), 8.33 (d, J=8.4 Hz,1H), 8.19 (d, J=1.6 Hz, 1H), 7.97 (dd, J=1.6, 8.4 Hz, 1H), 7.05 (q,J=8.0 Hz, 1H), 6.94 (br d, J=6.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),6.53-6.38 (m, 1H), 4.29-4.22 (m, 1H), 4.19 (br s, 1H), 4.12 (m, 1H),3.93-3.73 (m, 2H), 3.46-3.34 (m, 4H), 2.82-2.67 (m, 3H), 2.64-2.55 (m,1H), 2.19-2.03 (m, 3H), 1.98-1.87 (m, 1H), 1.81 (m, 2H), 1.77-1.61 (m,3H), 1.55 (s, 6H), 1.52-1.43 (m, 2H), 1.36 (d, J=6.0 Hz, 2H), 1.29 (m,2H), 1.21 (br d, J=6.4 Hz, 6H), 1.14-0.97 (m, 2H).

Example 33:2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of5-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.090 g, 0.160 mmol) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.094 g,0.320 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.14 mL, 0.800 mmol) and sodium iodide (0.024 g, 0.160 mmol) and thereaction solution was stirred at 80° C. After 12 h the reaction solutionwas diluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The resulting crude material was purified bystandard methods to provide2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.059 g, 0.070 mmol, 44% yield) as a grey solid. MS (ESI)m/z 825.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.54-10.38(m, 1H), 9.15 (m, 2H), 8.74 (d, J=1.6 Hz, 1H), 7.11-7.00 (m, 1H), 6.91(s, 1H), 6.85-6.77 (m, 1H), 6.51-6.41 (m, 1H), 4.30-4.22 (m, 1H), 4.17(br s, 1H), 4.09-4.02 (m, 1H), 3.90-3.78 (m, 1H), 3.64-3.57 (m, 1H),3.50 (br s, 2H), 3.41 (m, 2H), 2.84-2.68 (m, 3H), 2.64-2.56 (m, 1H),2.18-2.04 (m, 3H), 1.99-1.87 (m, 1H), 1.86-1.76 (m, 2H), 1.76-1.61 (m,3H), 1.57 (s, 6H), 1.51 (m, 2H), 1.35 (br d, J=6.4 Hz, 2H), 1.33-1.24(m, 2H), 1.21 (br d, J=6.4 Hz, 6H), 1.15-1.00 (m, 2H).

Example 34:2-((R)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((R)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of4-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(0.213 g, 0.410 mmol) andN-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide(0.180 g, 0.410 mmol) in DMF (1 mL) was added potassium iodide (68.16mg, 0.4100 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.23mmol) and the reaction solution was stirred at 50° C. After 12 h thereaction solution was diluted with water (30 mL) and extracted withethyl acetate (2×30 mL). the combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated. Theresulting crude material was purified by standard methods to provide2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.048 g, 0.054 mmol, 13% yield) as a green solid. MS (ESI) m/z 876.5[M+1]⁺; 1H NMR (400 MHz, DMSO-d6) δ 10.89-10.79 (m, 1H), 9.76 (s, 1H),8.34 (d, J=8.2 Hz, 1H), 8.20 (d, J=1.8 Hz, 1H), 7.98 (dd, J=1.7, 8.2 Hz,1H), 7.25-7.21 (m, 2H), 6.78 (s, 1H), 6.51 (d, J=8.2 Hz, 1H), 4.40 (ddd,J=4.7, 7.6, 12.3 Hz, 1H), 3.91-3.79 (m, 1H), 3.71-3.58 (m, 2H), 3.55 (t,J=5.7 Hz, 2H), 3.41 (d, J=16.6 Hz, 2H), 3.33-3.22 (m, 8H), 2.97-2.77 (m,4H), 2.10-2.01 (m, 3H), 1.96-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.55 (s,6H), 1.34-1.24 (m, 2H).

Example 35:2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile(0.120 g, 0.220 mmol) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.129 g,0.440 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.19 mL, 1.090 mmol) and sodium iodide (0.033 g, 0.220 mmol) and thereaction solution was stirred at 80° C. After 12 h the reaction solutionwas diluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The resulting crude material was purified ystandard methods to provide2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (0.086 g, 0.104 mmol, 47% yield) as a yellow solid. MS(ESI) m/z 811.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.80(s, 1H), 10.60 (s, 1H), 10.36-10.05 (m, 1H), 9.25-9.00 (m, 1H), 8.74 (d,J=2.0 Hz, 1H), 7.10-7.01 (m, 1H), 6.98 (br d, J=10.4 Hz, 1H), 6.86 (d,J=8.0 Hz, 1H), 6.52-6.39 (m, 1H), 4.30-4.23 (m, 1H), 4.22-4.14 (m, 2H),3.86-3.82 (m, 1H), 3.55-3.37 (m, 5H), 2.84-2.66 (m, 3H), 2.64-2.55 (m,1H), 2.22-2.12 (m, 1H), 2.12-2.02 (m, 2H), 1.98-1.86 (m, 1H), 1.81 (brd, J=12.0 Hz, 2H), 1.76-1.62 (m, 3H), 1.56 (s, 6H), 1.47-1.27 (m, 7H),1.22 (d, J=6.4 Hz, 3H), 1.17-1.01 (m, 2H).

Example 36:2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)aceticacid (0.120 g, 0.200 mmol) and3-((3-aminophenyl)amino)piperidine-2,6-dione (0.065 g, 0.300 mmol) inpyridine (2 mL) was added EDCI (0.070 g, 0.390 mmol) and the reactionsolution was stirred at 50° C. After 12 h the reaction solution wasdiluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).the combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The resulting crude material waspurified by standard methods to provide2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.071 g, 0.087 mmol, 44% yield) as a yellow solid. MS (ESI) m/z 810.3[M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.80 (s, 1H), 10.60(s, 1H), 10.42-10.12 (m, 1H), 9.13 (br s, 1H), 8.34 (d, J=8.0 Hz, 1H),8.20 (d, J=2.0 Hz, 1H), 7.97 (dd, J=1.6, 8.4 Hz, 1H), 7.11-7.01 (m, 1H),6.98 (br d, J=10.0 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.57-6.36 (m, 1H),4.25 (m, 1H), 4.19 (m, 2H), 3.88-3.79 (m, 1H), 3.71-3.62 (m, 1H),3.58-3.39 (m, 4H), 2.83-2.64 (m, 3H), 2.63-2.55 (m, 1H), 2.21-2.02 (m,3H), 1.91 (m, 1H), 1.81 (br d, J=12.4 Hz, 2H), 1.76-1.62 (m, 3H), 1.55(s, 6H), 1.47-1.28 (m, 7H), 1.22 (d, J=6.4 Hz, 3H), 1.16-0.99 (m, 2H).

Example 37:N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((trans)-4-(3-((1r,4S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamide

N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamidehydrochloride. To a flask containing 22-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (100. mg, 0.1600 mmol), and3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione hydrochloride(52.52 mg, 0.1800 mmol) was added MeCN (1 mL), 1-methylimidazole (0.05mL, 0.6600 mmol), andN-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture wasstirred at 25° C. for 30 min. The reaction was diluted with DMSO (1.0mL) and purified by standard methods to provideN-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetamidehydrochloride (76.9 mg, 0.0858 mmol, 52% yield) as a grey solid. MS(ESI) m/z 844.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.34(d, J=8.31 Hz, 1H), 8.19 (d, J=1.59 Hz, 1H), 7.97 (dd, J=1.65, 8.25 Hz,1H), 6.96 (s, 1H), 6.90 (br s, 1H), 6.49 (s, 1H), 4.34 (br dd, J=4.89,11.62 Hz, 5H), 3.74-3.92 (m, 3H), 3.52-3.65 (m, 2H), 2.90-3.11 (m, 4H),2.68-2.83 (m, 3H), 2.54-2.63 (m, 1H), 2.01-2.11 (m, 1H), 1.88-1.97 (m,1H), 1.80-1.88 (m, 2H), 1.74 (br d, J=9.29 Hz, 4H), 1.49-1.61 (m, 6H),1.16-1.33 (m, 9H), 1.01-1.15 (m, 2H).

Example 38:2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide

2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide.To a flask containing 22-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (100 mg, 0.1600 mmol), and3-((3-amino-5-fluorophenyl)amino)piperidine-2,6-dione (42.9 mg, 0.1800mmol) was added MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol),and N-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture wasstirred at 25° C. for 30 min. The reaction was diluted with DMSO (1.0mL) and purified by standard methods to provide2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamidehydrochloride (70.4 mg, 0.08 mmol, 49% yield) as an off-white solid. MS(ESI) m/z 827.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.34(d, J=8.19 Hz, 1H), 8.19 (d, J=1.59 Hz, 1H), 7.97 (dd, J=1.59, 8.19 Hz,1H), 6.67-6.81 (m, 2H), 6.27 (br d, J=11.98 Hz, 1H), 4.31 (br dd,J=4.89, 11.62 Hz, 1H), 2.93-3.11 (m, 4H), 2.68-2.82 (m, 3H), 2.55-2.62(m, 1H), 2.03-2.13 (m, 2H), 1.87-1.97 (m, 1H), 1.80-1.87 (m, 2H),1.68-1.80 (m, 4H), 1.51-1.59 (m, 6H), 1.16-1.33 (m, 9H), 1.02-1.15 (m,3H).

Example 39:2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide

2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamidehydrochloride. To a flask containing 22-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)aceticacid (100 mg, 0.1600 mmol), and3-((3-amino-4-fluorophenyl)amino)piperidine-2,6-dione (42.9 mg, 0.1800mmol) was added MeCN (1 mL), 1-methylimidazole (0.05 mL, 0.6600 mmol),and N-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (92.34 mg, 0.3300 mmol). The reaction mixture wasstirred at 25° C. for 30 min. The reaction was diluted with DMSO (1.0mL) and purified by standard methods to provide2-((2R,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamidehydrochloride hydrochloride (66 mg, 0.076 mmol, 46% yield) as a tansolid. MS (ESI) m/z 827.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s,1H), 8.34 (d, J=8.19 Hz, 1H), 8.19 (d, J=1.59 Hz, 1H), 7.97 (dd, J=1.65,8.25 Hz, 1H), 7.21 (br d, J=3.67 Hz, 1H), 7.01 (t, J=9.78 Hz, 1H),6.38-6.54 (m, 1H), 4.24 (br dd, J=4.77, 11.25 Hz, 2H), 3.02 (br s, 3H),2.68-2.82 (m, 3H), 2.54-2.64 (m, 1H), 2.02-2.13 (m, 1H), 1.87-1.95 (m,1H), 1.84 (br d, J=11.37 Hz, 2H), 1.68-1.79 (m, 4H), 1.50-1.59 (m, 6H),1.16-1.31 (m, 8H), 1.02-1.16 (m, 3H).

Example 40:2-((S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (40. mg, 0.0600 mmol) was combined with 33-((3-aminophenyl)amino)piperidine-2,6-dione (16.2 mg, 0.0700 mmol),1-methylimidazole (0.03 mL, 0.3100 mmol),N-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (38.01 mg, 0.1400 mmol), and MeCN (0.7738 mL) andDMF (0.7738 mL) and the reaction was stirred at 25° C. After 18 h thereaction solution was diluted with water and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,concentrated, and the resulting crude material was purified by standardmethods to provide2-((S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(9 mg, 0.01 mmol, 16% yield) as a yellow solid. MS (ESI) m/z 851.3[M+1]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.9-11.0 (m, 1H), 10.6-10.8 (m,1H), 9.5-9.7 (m, 1H), 8.2-8.3 (m, 1H), 8.0-8.2 (m, 1H), 7.8-8.0 (m, 1H),6.9-7.0 (m, 2H), 6.7-6.8 (m, 1H), 6.2-6.4 (m, 1H), 4.4-4.7 (m, 6H),4.2-4.2 (m, 1H), 3.7-3.9 (m, 3H), 3.6-3.7 (m, 1H), 3.5-3.6 (m, 1H),3.4-3.5 (m, 1H), 3.2-3.3 (m, 2H), 3.0-3.1 (m, 2H), 2.6-2.9 (m, 3H),2.5-2.6 (m, 1H), 2.0-2.1 (m, 3H), 1.8-1.9 (m, 1H), 1.6-1.7 (m, 2H),1.4-1.5 (m, 6H), 1.2-1.3 (m, 2H).

Example 41:2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (5.000 g, 7.68 mmol) and(S)-3-((3-aminophenyl)amino)piperidine-2,6-dione (1.850 g, 8.45 mmol) inDMF (50 mL) was added HATU (2.920 g, 7.68 mmol) andN-ethyl-N-isopropylpropan-2-amine (4.01 mL, 23.05 mmol) and the reactionsolution was stirred at room temperature. After 12 h the reactionsolution was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The resulting crude material waspurified by standard methods to provide2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (1539.8 mg, 1.78 mmol, 23% yield) as yellow solid. MS(ESI) m/z 852.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.15 (m, 1H),10.80 (s, 1H), 9.87-9.63 (m, 1H), 9.14 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.0Hz, 1H), 7.14-6.97 (m, 2H), 6.94-6.78 (m, 1H), 6.44 (d, J=8.0 Hz, 1H),4.42 (s, 1H), 4.35-4.21 (m, 1H), 3.89 (s, 3H), 3.71 (d, J=11.2 Hz, 1H),3.60 (s, 2H), 3.51 (d, J=11.2 Hz, 2H), 3.36 (d, J=10.8 Hz, 4H),3.25-3.08 (m, 3H), 2.93-2.79 (m, 2H), 2.77-2.68 (m, 1H), 2.65-2.55 (m,1H), 2.16-2.04 (m, 3H), 1.96-1.86 (m, 1H), 1.72 (d, J=10.0 Hz, 2H), 1.57(s, 6H), 1.44-1.35 (m, 2H).

Example 42:2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)aceticacid (5.000 g, 7.685 mmol) and(R)-3-((3-aminophenyl)amino)piperidine-2,6-dione (1.853 g, 8.450 mmol)in DMF (50 mL) was added HATU (2.922 g, 7.680 mmol) andN,N-diisopropylethylamine (4 mL, 23.05 mmol) and the reaction solutionwas stirred at room temperature. After 12 h the reaction solution wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The resulting crude material was purified bystandard methods to provide2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (4.594 g, 5.376 mmol, 70% yield) as an off white solid. MS(ESI) m/z 852.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (br s, 1H),10.80 (s, 1H), 9.76-9.56 (m, 1H), 9.16 (d, J=1.6 Hz, 1H), 8.76 (d, J=1.6Hz, 1H), 7.04-6.94 (m, 2H), 6.80 (br d, J=8.0 Hz, 1H), 6.40 (br d, J=8.0Hz, 1H), 4.41 (br s, 1H), 4.24 (br dd, J=4.4, 11.2 Hz, 1H), 3.87 (br s,3H), 3.72 (br d, J=11.2 Hz, 1H), 3.61 (br s, 2H), 3.52 (br s, 2H),3.45-3.26 (m, 1H), 3.36 (br s, 3H), 3.12 (br d, J=10.4 Hz, 3H), 2.88 (brd, J=11.2 Hz, 2H), 2.79-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.08 (br dd,J=4.0, 8.8 Hz, 3H), 1.96-1.85 (m, 1H), 1.72 (br d, J=10.0 Hz, 2H), 1.57(s, 6H), 1.42-1.31 (m, 2H).

Example 43:2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)aceticacid (0.080 g, 0.130 mmol) and3-((3-aminophenyl)amino)piperidine-2,6-dione (0.042 g, 0.190 mmol) inpyridine (2 mL) was added EDCI (0.098 g, 0.510 mmol) and the reactionsolution was stirred at 60° C. After 12 h the reaction solution wasdiluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).the combined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate and concentrated. The resulting crude materialwas purified by standard methods to provide2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.048 g, 0.0555 mmol, 43% yield) as a green solid. MS (ESI) m/z 826.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 9.48-9.39 (s, 1H),8.33 (d, J=8.4 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 8.03-7.91 (m, 1H),7.06-6.93 (m, 2H), 6.85-6.77 (m, 1H), 6.45-6.32 (m, 1H), 5.87 (d, J=8.0Hz, 1H), 4.34-4.20 (m, 1H), 3.93-3.72 (m, 1H), 3.51 (s, 4H), 3.15 (s,2H), 2.89-2.75 (m, 2H), 2.74-2.63 (m, 3H), 2.62-2.54 (m, 1H), 2.13-1.98(m, 3H), 1.95-1.82 (m, 3H), 1.71 (br d, J=11.2 Hz, 2H), 1.54 (s, 6H),1.39-1.29 (m, 2H), 1.28-1.18 (m, 2H), 1.18-1.09 (m, 2H), 1.05 (d, J=6.2Hz, 6H).

Example 44:2-(4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

tert-Butyl-4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl-5,5-difluoropiperidine-1-carboxylate.To a solution of tert-butyl3,3-difluoro-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate(1.81 g, 5.27 mmol) in xylenes (30 mL) was added(trans4-(dibenzylamino)cyclohexan-1-ol (3.11 g, 10.54 mmol),tetrabutylammonium bromide (0.340 g, 1.054 mmol), and potassiumhydroxide (1.479 g, 26.4 mmol). The reaction mixture was heated to 30°C. for 24 h. The reaction mixture was partitioned between water andethyl acetate. The organic layer was removed and the aqueous layer wasextracted with ethyl acetate twice more. The combined organic layer waswashed with brine, dried over sodium sulfate, and filtered. The filtratewas taken and volatile organics were removed under reduced pressure togive a light yellow solid. The solid was taken up in ethyl acetate andpurified on a silica gel column using 0-75% ethyl acetate in hexanesover 2000 mL. Fractions containing desired product were combined andvolatile organics were removed under reduced pressure to give tert-butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.79 g, 3.30 mmol, 63% yield) as a colorless oil. MS (ESI) m/z 543.2[M+1]⁺.

tert-Butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.To a solution of tert-butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(2.65 g, 4.88 mmol) in Methanol (50 ml) was added palladium on carbon(500 mg, 4.70 mmol). Air in the flask was evacuated and replaced withhydrogen (3×, 15 psi, balloon). The reaction mixture was stirred atambient temperature for 18 h. The reaction was filtered through celite.The filter cake was washed with more methanol. The filtrate was takenand volatile organics were removed under reduced pressure to givetert-butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.72 g, 4.75 mmol, 97% yield) as a light yellow oil. MS (ESI) m/z 363.2[M+1]⁺.

tert-Butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate.To a solution of tert-butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.72 g, 4.75 mmol) in acetonitrile (20 ml) was added methyl2-bromo-2-methylpropanoate (1.718 g, 9.49 mmol), potassium iodide (0.079g, 0.475 mmol), and potassium carbonate (1.312 g, 9.49 mmol). Thereaction mixture was stirred at 110° C. for 20 h. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer wasremoved and the aqueous layer was extracted with ethyl acetate twicemore. The combined organic layer was washed with brine, dried oversodium sulfate, and filtered. The filtrate was taken and volatileorganics were removed under reduced pressure to give tert-butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate(2.20 g, 4.76 mmol) as a yellow oil, which was carried forward withoutfurther purification. MS (ESI) m/z 463.2 [M+1]⁺.

tert-Butyl-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.To a solution of tert-butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate(0.730 g, 1.578 mmol) in ethyl acetate (7 mL) was added4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.360 g, 1.578 mmol)and diisopropylethylamine (0.827 mL, 4.73 mmol). The reaction vial wassealed and stirred at 90° C. for 18 h. The reaction mixture waspartitioned between water and ethyl acetate. 5 mL of brine were added toreduce emulsion. The organic layer was removed and the aqueous layer wasextracted with ethyl acetate twice more. The combined organic layer waswashed with brine, dried over sodium sulfate, and filtered. The filtratewas taken and volatile organics were removed under reduced pressure togive a foamy dark orange semi-solid. The solid was taken up in ethylacetate and purified on a silica gel column using 0-100% ethyl acetatein hexanes over 1000 mL. Fractions containing desired product werecombined and volatile organics were removed under reduced pressure togive tert-butyl4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(396 mg, 0.601 mmol, 38% yield) as a foamy orange semi-solid. MS (ESI)m/z 559.2 [M-99]⁺.

4-(3-((trans)-4-(2-(3,3-Difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrilehydrochloride. To a solution of4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile,HCl (395 mg, 0.664 mmol, 110% yield) in 1,4-Dioxane (3.0 ml) was addedHCl (2.0 ml, 8.00 mmol) (4.0 M in dioxane). The reaction was stirred atambient temperature for 90 min. Volatile organics were removed underreduced pressure to give4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrilehydrochloride (395 mg, 0.664 mmol) as a foamy orange semi-solid that wascarried forward without further purification. MS (ESI) m/z 559.2 [M+1]⁺.

2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a solution of4-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile(100 mg, 0.179 mmol) and2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (68.8 mg,0.233 mmol) in N,N-dimethylformamide (2 mL, 0.09 M) was addeddiisopropylethylamine (0.094 mL, 0.537 mmol) and sodium iodide (0.027 g,0.180 mmol, 1 equiv.). The reaction solution was stirred at 80° C. After22 h the reaction solution was diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (30 mL), dried over anhydrous sodium sulfate, andconcentrated. The crude material was purified by standard methods togive2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(55 mg, 0.066 mmol, 37% yield). MS (ESI) m/z 818.2 [M+1]⁺; ¹H NMR(DMSO-d6, 400 MHz) δ 10.7-10.9 (m, 1H), 10.2-10.4 (m, 1H), 8.3-8.4 (m,1H), 8.2-8.2 (m, 1H), 7.9-8.0 (m, 1H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H),6.7-6.9 (m, 1H), 6.4-6.5 (m, 1H), 4.2-4.3 (m, 1H), 3.9-4.2 (m, 2H),3.8-3.9 (m, 2H), 3.2-3.3 (m, 3H), 2.7-2.9 (m, 3H), 2.6-2.7 (m, 1H),2.2-2.3 (m, 2H), 2.0-2.2 (m, 4H), 1.9-2.0 (m, 2H), 1.6-1.8 (m, 3H),1.5-1.6 (m, 6H), 1.4-1.5 (m, 1H), 1.3-1.4 (m, 2H), 1.2-1.3 (m, 2H).

Example 45:2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide

2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.To a mixture of2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)aceticacid (0.100 g, 0.160 mmol) in Pyridine (2 mL) was added3-((3-aminophenyl)amino)piperidine-2,6-dione (0.042 g, 0.190 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.02 mL, 0.640 mmol) andthe reaction solution was heated to 50° C. After 8 h the reactionsolution was diluted with water (80 mL) and extracted with ethyl acetate(3×30 mL). the combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated. The crude material waspurified by standard methods to provide2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide(0.070 g, 0.083 mmol, 52% yield) as a yellow solid MS (ESI) m/z 827.6[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 9.41 (s, 1H), 9.15(d, J=2.0 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 7.02-6.97 (m, 2H), 6.82 (d,J=7.6 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 5.89 (d, J=8.0 Hz, 1H), 4.32-4.26(m, 1H), 3.84 (d, J=8.0 Hz, 1H), 3.52 (s, 4H), 3.32-3.23 (m, 2H), 3.16(s, 2H), 2.81 (m, 2H), 2.74-2.65 (m, 3H), 2.63-2.58 (m, 1H), 2.10-2.02(m, 3H), 1.92-1.85 (m, 3H), 1.74-1.68 (m, 2H), 1.57 (s, 6H), 1.34 (d,J=12.0 Hz, 2H), 1.14 (q, J=11.2 Hz, 2H), 1.05 (d, J=6.4 Hz, 6H).

Example 46:2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride

tert-Butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.To a solution of tert-butyl3,3-difluoro-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate(1.81 g, 5.27 mmol) in xylenes (30 mL) was added(1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (3.11 g, 10.54 mmol),tetrabutylammonium bromide (0.340 g, 1.054 mmol), and potassiumhydroxide (1.479 g, 26.4 mmol). The reaction mixture was heated to 30°C. for 24 h. The reaction mixture was partitioned between water andethyl acetate. The organic layer was removed and the aqueous layer wasextracted with ethyl acetate twice more. The combined organic layer waswashed with brine, dried over sodium sulfate, and filtered. The filtratewas taken and volatile organics were removed under reduced pressure togive a light yellow solid. The solid was taken up in ethyl acetate andpurified on a silica gel column using 0-75% ethyl acetate in hexanesover 2000 mL. Fractions containing desired product were combined andvolatile organics were removed under reduced pressure to give tert-butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.79 g, 3.30 mmol, 63% yield) as a colorless oil. MS (ESI) m/z 543.2[M+1]⁺.

tert-Butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.To a solution of tert-butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(2.65 g, 4.88 mmol) in Methanol (50 ml) was added palladium on carbon(500 mg, 4.70 mmol). Air in the flask was evacuated and replaced withhydrogen (3×, 15 psi, balloon). The reaction mixture was stirred atambient temperature for 18 h. The reaction was filtered through celite.The filter cake was washed with more methanol. The filtrate was takenand volatile organics were removed under reduced pressure to givetert-butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.72 g, 4.75 mmol, 97% yield) as a light yellow oil. MS (ESI) m/z 363.2[M+1]⁺.

tert-Butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate.To a solution of tert-butyl4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.72 g, 4.75 mmol) in acetonitrile (20 ml) was added methyl2-bromo-2-methylpropanoate (1.718 g, 9.49 mmol), potassium iodide (0.079g, 0.475 mmol), and potassium carbonate (1.312 g, 9.49 mmol). Thereaction mixture was stirred at 110° C. for 20 h. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer wasremoved and the aqueous layer was extracted with ethyl acetate twicemore. The combined organic layer was washed with brine, dried oversodium sulfate, and filtered. The filtrate was taken and volatileorganics were removed under reduced pressure to give tert-butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate(2.20 g, 4.76 mmol) as a yellow oil, which was carried forward withoutfurther purification. MS (ESI) m/z 463.2 [M+1]⁺.

tert-Butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate.To a solution of tert-butyl3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate(1.47 g, 3.18 mmol) in ethyl acetate (14 mL) was added5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.728 g, 3.18 mmol)and diisopropylethylamine (1.665 mL, 9.53 mmol). The reaction vial wassealed and stirred at 90° C. for 18 h. The reaction mixture waspartitioned between water and ethyl acetate. A few mL of brine wereadded to reduce emulsion. The organic layer was removed and the aqueouslayer was extracted with ethyl acetate twice more. The combined organiclayer was washed with brine, dried over sodium sulfate, and filtered.The filtrate was taken and volatile organics were removed under reducedpressure to give a foamy dark orange semi-solid. The solid was taken upin ethyl acetate and purified on a silica gel column using 0-100% ethylacetate in hexanes over 1800 mL. Fractions containing desired productwere combined and volatile organics were removed under reduced pressureto give tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.10 g, 1.667 mmol, 52% yield) as a foamy light orange semi-solid. MS(ESI) m/z 560.2 [M-99]⁺.

5-(3-((trans)-4-(2-(3,3-Difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrilehydrochloride. To a solution of tert-butyl4-(2-(((1r,4r)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate(1.10 g, 1.667 mmol) in 1,4-dioxane (5.0 ml) was added HCl (5.0 ml,20.00 mmol) (4.0 M in dioxane). The reaction was stirred at ambienttemperature for 90 min. Volatile organics were removed under reducedpressure to give5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrilehydrochloride (1.08 g, 1.812 mmol) as a foamy orange semi-solid that wascarried forward without further purification. MS (ESI) m/z 560.2 [M+1]⁺.

2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate.To a solution of5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile,HCl (1.08 g, 1.812 mmol) in acetonitrile (15 mL) was added triethylamine(0.758 mL, 5.44 mmol) and tert-butyl 2-bromoacetate (1.338 mL, 9.06mmol). The reaction vessel was sealed and stirred at 70° C. for 18 h.Volatile organics were removed under reduced pressure to give an orangesolid. Solid was taken up in dichloromethane and purified on a silicagel column using 0-100% ethyl acetate in hexanes over 2200 mL. Fractionscontaining desired product were combined and volatile organics wereremoved under reduced pressure to give tert-butyl2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate(0.997 g, 1.480 mmol, 82% yield) as a foamy orange semi-solid. MS (ESI)m/z 674.2 [M+1]⁺.

2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)aceticacid hydrochloride. To a flask containing tert-butyl2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate(1.0 g, 1.484 mmol) was added HCl (10.0 ml, 40.0 mmol) (4.0 M indioxane). The reaction mixture was stirred at ambient temperature for 3h. Volatile organics were removed under reduced pressure to give2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)aceticacid hydrochloride (1.14 g, 1.743 mmol) as a light brown solid which wascarried forward without further purification. MS (ESI) m/z 618.2 [M+1]⁺.

2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride. To a solution of2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)aceticacid, HCl (100 mg, 0.153 mmol) in Acetonitrile (1.0 mL) was added3-((3-aminophenyl)amino)piperidine-2,6-dione (40.2 mg, 0.183 mmol),1-methyl-1H-imidazole (0.049 mL, 0.612 mmol),N-(chloro(dimethylamino)methylene)-N-methylmethanaminiumhexafluorophosphate (86 mg, 0.306 mmol) and 1 mL DMF and the reactionsolution was stirred at room temperature. After 18 h the reactionsolution was diluted with DMSO and purified by standard methods toprovide2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamidehydrochloride (50 mg, 0.058 mmol, 38% yield) as a white solid. MS (ESI)m/z 819.2 [M+1]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.79 (s, 1H), 9.14 (d,1H, J=2.0 Hz), 8.74 (d, 1H, J=2.0 Hz), 7.0-7.1 (m, 1H), 6.95 (s, 1H),6.8-6.8 (m, 1H), 6.45 (dd, 1H, J=1.5, 8.1 Hz), 4.26 (dd, 1H, J=4.6, 11.2Hz), 4.0-4.2 (m, 1H), 3.8-3.9 (m, 1H), 3.7-3.8 (m, 1H), 3.4-3.6 (m, 3H),3.3-3.4 (m, 1H), 3.2-3.3 (m, 1H), 3.0-3.2 (m, 1H), 2.7-2.9 (m, 3H),2.6-2.6 (m, 1H), 2.0-2.1 (m, 4H), 1.8-2.0 (m, 2H), 1.6-1.8 (m, 3H), 1.57(s, 6H), 1.4-1.5 (m, 1H), 1.3-1.4 (m, 2H).

Assays Cell Based Assays

VCAP AR Degradation Assay. Test compounds were pre-dispensed into aCorning CellBind 96-well clear bottom plate (Cat #3300) using anacoustic dispenser to make a 10-point concentration series at 1:3dilution for each compound. The final top concentration of each compoundwas 5 μM. DMSO at a final concentration of 0.1% was used as a control.VCaP cells cultured in DMEM with 8% fetal bovine serum (FBS) were seededat 50K cells per well in a 200 μL volume into the compound plate andincubated at 37° C. in a CO₂ incubator for 24 h. The medium wascarefully removed from the cells and the plate was placed on ice. Onehundred μL of ice-cold 1× cell lysis buffer from Cell SignalingTechnologies (Cat #9803) was added to each well of the cells and theplate was incubated at 4° C. on a shaker for 1 h. Fifteen μL of celllysate was used for AR ELISA detection using a PathScan Total SandwichAR ELISA kit (Cell Signaling Technology, Cat #12580). AR levels incompound-treated wells were normalized to that of DMSO control andexpressed as percent of control (PoC) (y). A Four Parameter LogisticModel (Sigmoidal Dose-Response Model) was used to determine thecompound's DC₅₀, and EC₅₀, using the following equation:

y=(A+((B−A)/(1+((C/x){circumflex over ( )}D))))

-   -   A=Y_(Min) (lowest AR level normalized to DMSO control in        response to compound treatment, as determined by curve fit)    -   B=Y_(Max) (maximum AR level as determined by curve fit)    -   C=EC₅₀    -   D=Hill Slope    -   x=compound concentration    -   EC₅₀=the concentration of compound when y=(Y_(Max)−Y_(Min))/2    -   DC₅₀=the concentration of the compound when y=50% of DMSO        control (50% AR degradation)    -   y=AR protein level normalized to DMSO control

The lowest measured AR level normalized to DMSO control in response tocompound treatment, termed Y value, was used to characterize thecompound-mediated AR degradation efficiency.

Each of the compounds in Table 1, was tested in the VCAP AR degradationassay, and was found to have activity therein. All of the compounds inTable 1 were shown to have an DC₅₀<1 μM and Y<50% of DMSO control.

Prostate Cancer Cell Proliferation Assay. VCAP or ENZR cells were platedat 10K cells per well in 96-well CellBind (Costar) plates using DMEM+8%FBS media. Cells were incubated overnight at 37° C. and test compoundwas serially diluted and added to the well. Following seven-dayincubation, the assay media was removed by inversion and the plate wasfrozen overnight at −80° C. Plates were thawed at room temperature and100 μL deionized water (ddH₂O) was added to each well. Plates wereincubated at 37° C. in non-CO₂ incubator for 1 h and then frozen at −80°C. overnight. Plates were thawed to room temperature and 100-μL TNEbuffer (NaCl, Tris, EDTA)+Hoescht dye (1.0 mg/ml, 1:400) was added toeach well. Fluorescent signal was measured at 460 nm. All data werenormalized as a percentage of the DMSO control. A Four ParameterLogistic Model (Sigmoidal Dose-Response Model) was used to determine thecompound's GI₅₀ value, using the following equation:

y=(A+((B−A)/(1+((C/x){circumflex over ( )}D))))

-   -   A=Y_(Min) (lowest cell viability in luminescence unit normalized        to DMSO control in response to compound treatment determined by        curve fit)    -   B=Y_(Max) (maximum cell viability measured as luminescence unit        normalized to DMSO control as determined by curve fit)    -   C=EC₅₀    -   D=Hill Slope    -   GI₅₀=the concentration of the compound when Y=(Y_(Max)+Y_(t) ₀        )/2    -   EC₅₀=the concentration of compound when y=(Y_(Max)−Y_(Min))/2    -   IC₅₀=the concentration of the compound when Y=50% of DMSO        control    -   y=cell viability measured as luminescence unit and normalized as        percentage of the DMSO control    -   t₀=time when compound was added    -   Y_(t) ₀ =value of y at t0

The compounds provided herein have been, or will be tested in theprostate cancer cell proliferation assay, and have shown, or will beshown, to have activity therein.

In Vivo Assays

AR Degradation Assay. In vivo AR degradation assays were performed inNSG mice bearing VCaP prostate cancer xenograft tumors. Male NSG micewere inoculated with VCaP cells in the flank region above the right leg.Following inoculation of the animals, the tumors were allowed to grow toapproximately 500 mm³ prior to randomization. The randomized animalswere administered with test compounds formulated in 20% Labrasol, 80% 25mM citrate buffer pH 3. The compounds were administered orally oncedaily for 3 days. After the last dose of compound administration, theplasma and tumors were collected and processed for AR degradationassays. Intratumoral AR levels were measured using western blotanalysis. Statistical analysis was performed using a one-way analysis ofvariance (ANOVA).

The compounds provided herein have been, or will be tested in the invivo AR degradation assay, and have shown, or will be shown, to haveactivity therein.

VCaP Prostate Cancer Xenograft model. The xenograft study was conductedwith male NSG mice bearing VCaP prostate cancer xenograft tumors. MaleNSG mice were inoculated subcutaneously with VCaP cells in the flankregion above the right hind leg. Following inoculation of the animals,the tumors were allowed to grow to approximately 200 mm³ prior torandomization. During randomization, the mice bearing VCaP tumorsranging between 75 and 250 mm³ were pooled together and randomized intovarious treatment groups. Test compounds formulated in 20% Labrasol, 80%25 mM citrate buffer pH 3 were administered in a dose volume of 5 mL/kg.The compounds were administered orally once daily for the duration ofthe study. Tumors were measured twice a week using calipers and tumorvolumes were calculated using the formula W²×L/2. Statistical analysiswas performed using a one-way or two-way analysis of variance (ANOVA).

The compounds provided herein have been, or will be tested in the VCAPprostate cancer xenograft model and have shown, or will be shown, to beeffective as treatments of prostate cancer in the models.

Activity Table

Each of the compounds in Table 1, was tested in one or more of the ARdegradation assays shown above, for example, the VCAP AR DegradationAssay, and was found to have activity therein.

All of the compounds in Table 1 were shown to have a DC₅₀≤1 μM and Y<50%of DMSO control, with some compounds having a DC₅₀ value C: DC₅₀≤0.005μM, some a DC₅₀ value B: 0.005 μM<DC₅₀≤0.010 μM, and others a DC₅₀ valueA: 0.010 μM<DC₅₀≤0.1 μM.

Additionally the compounds were shown to have an AR degradationefficiency Y value <50% of DMSO control, with some compounds having0<Y≤15% (shown as *), some compounds having 15%<Y≤20% (shown as **), andothers having 25%<Y<50% (shown as ***),

TABLE 1 Cmpd MH⁺ No. Cmpd Structure Cmpd Name Obs. DC₅₀ Y 1

2-((2R,6S)-4-(2-((trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1- yl)-N-(3-(2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 811.3 B *** 2

2-((2S,6R)-4-(3-(trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 809.4 A * 3

2-((2R,6S)-4-(2-((trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1- yl)-N-(3-((R)-2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 811.4 B *** 4

2-((2R,6S)-4-(2-((trans-4- (3-(3-chloro-4- cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1- yl)-N-(3-(2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 777.4 C ** 5

2-((2R,6S)-4-(2-((trans-4- (3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperazin-1- yl)-N-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 812.0 C *** 6

2-((2R6S)-4-(3-(trans-4- (3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-(((7?)-2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 809.4 B * 7

2-((2R,6S)-4-(2-((trans-4- (3-(4-cyano-3- (pentafluoro-A6-sulfaneyl)phenyl)-5,5- dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperazin-1- yl)-N-(3-(2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 869.2 A *** 8

2-((2R,6S)-4-(3-(trans-4- (3-(5-chloro-6- cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 778.3 B *** 9

2-((2R,6S)-4-(3-((trans-4- (3-(3-chloro-4- cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1- yl)-N-(3-(2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 791.3 C *** 10

2-((2R,6S)-4-(3-((trans-4- (3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)- 2,6-dimethylpiperazin-1- yl)-N-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 826.4 C ** 11

2-((2R6S)-4-(3-(trans-4- (3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6- dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 810.3 C * 12

2-((2R,6S)-4-(3-((trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1- yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 825.3 B *** 13

2-((2R6S)-4-(3-(trans-4- (3-(5-chloro-6- cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 776.4 B *** 14

2-((2S,6R)-4-(3-(trans-4- (3-(3-chloro-4- cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 775.6 A *** 15

2-((2R,4s,6S)-4-(2-((trans- 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1- yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 810.3 B * 16

2-((2R,4r,6S)-4-(2-((trans- 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1- sl)-N-(3-(2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 810.3 B * 17

2-((2R,6S)-4-(4-(trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 823.3 A *** 18

2-((2R,6S)-4-(3-(trans-4- (3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- G3-((CS)-2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 809.4 A ** 19

2-((R)-4-(2-((trans-4-(3-(4- cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)- 2-(trifluoromethyl)piperazin- 1-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 851.2 B * 20

2-((R)-4-(2-((trans-4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin-1-yl)-N-(3-((2,6- dioxopiperidin-3- yl)amino)phenyl)acetamide 852.2 C *21

2-((2S,4r,6R)-4-(2-((trans- 4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperidin-1- yl)-N-(3-(2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 811.3 C * 22

2-((2S,4s,6R)-4-(2-((trans- 4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperidin-1- yl)-N-(3-(2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 811.3 C * 23

2-((R)-4-(2-((trans-4-(3-(4- cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)- 2-(trifluoromethyl)piperazin- 1-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)-5- fluorophenyl)acetamide 869.6 B * 24

2-((R)-4-(2-((trans-4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin-1-yl)-N-(3-((2,6- dioxopiperidin-3- yl)amino)-5- fluorophenyl)acetamide870.6 C * 25

2-((R)-4-(3-(trans-4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin- 1-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 850.3 B * 26

N-(3-chloro-5-((2,6- dioxopiperidin-3- yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin- l-yl)acetamide886.0 B * 27

N-(3-Chloro-5-((2,6- dioxopiperidin-3- yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)- 2-(trifluoromethyl)piperazin- l-yl)acetamide 885.0 A * 28

2-((R)-4-(3-((trans-4-(3-(6- cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)- 2- (trifluoromethyl)piperazin-1-yl)-N-(3-((2,6- dioxopiperidin-3- yl)amino)phenyl)acetamide 866.3 C *29

2-((R)-4-(3-(trans-4-(3-(4- cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin- 1-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 849.3 B * 30

2-((R)-4-(3-((trans-4-(3-(4- cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)propyl)-2- (trifluoromethyl)piperazin- 1-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 865.5 B * 31

N-(3-cyano-5-((2,6- dioxopiperidin-3- yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin- l-yl)acetamide877.5 C * 32

2-((2R,4r,6S)-4-(3-(trans- 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1- yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 824.4 A ** 33

2-((2R,4r,6S)-4-(3-(trans- 4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1- yl)-N-(3-(2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 825.3 B ** 34

2-((R)-4-(2-((trans-4-(3-(4- cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)- 2-(trifluoromethyl)piperazin- 1-yl)-N-(3-cyano-5-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 876.5 B *** 35

2-((2R,4r,6S)-4-(2-(trans- 4-(3-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6- dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 811.3 A * 36

2-((2R,4r,6S)-4-(2-(trans- 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 810.3 A ** 37

2-((2R,4r,6S)-4-(2-((trans)- 4-(3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N- (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 844.2 A * 38

2-((2R,6S)-4-(3-((trans)-4- (3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (3-((2,6-dioxopiperidin-3- yl)amino)-5-fluorophenyl)acetamide 827.4 B * 39

2-((2R,6S)-4-(3-((trans)-4- (3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N- (5-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)acetamide 827.4 A *** 40

2-((S)-4-(2-(((trans)-4-03- (4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)- 2-(trifluoromethyl)piperazin- l-yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 851.3 A *** 41

2-((R)-4-(2-(((trans)-4-(3- (6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin-l-yl)-N-(3-(((S)-2,6- dioxopiperidin-3- yl)amino)phenyl)acetamide 852.0C * 42

2-((R)-4-(2-(((trans)-4-(3- (6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2- (trifluoromethyl)piperazin-l-yl)-N-(3-(((R)-2,6- dioxopiperidin-3- yl)amino)phenyl)acetamide 852.1C * 43

2-((2R,4r,6S)-4-(2- (((trans)-4-(3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1- yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 826.2 B *** 44

2-(4-(2-(((trans)-4-(3-(4- Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)- N-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)acetamide 818.2 B * 45

2-((2R,4r,6S)-4-(2- (((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3- yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1- yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1- yl)-N-(3-((2,6- dioxopiperidin-3-yl)amino)phenyl)acetamide 827.6 C ** 46

2-(4-(2-(((trans)-4-(3-(6- Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin- 3- yl)amino)phenyl)acetamide hydrochloride819.2 C * 47

2-((2R,6S)-4-(2-(((trans)- 4-(3-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperazin-1- yl)-N-(3-(((S)-2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 812.4 D * 48

2-((2R,6S)-4-(2-(((trans)- 4-(3-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)- 2,6-dimethylpiperazin-1- yl)-N-(3-(((R)-2,6-dioxopiperidin-3- yl)amino)phenyl)acetamide 812.2 D *

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A compound of formula I

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein R^(N) is H; n is 0-4; each R¹ isindependently selected from halogen, CN, and C₁₋₃ alkyl; a is 1 or 2; R²and R³ are each independently selected from H, and C₁₋₃ alkyl, or R² andR³ and the carbon to which they are attached form a substituted orunsubstituted C₃₋₆ cycloalkyl; m is 0-8; each R⁴ is independentlysubstituted or unsubstituted C₁₋₃ alkyl, or two R⁴ groups, together withthe same carbon atom or adjacent carbon atoms to which they areattached, form a substituted or unsubstituted C₃₋₆ cycloalkyl, or two R⁴groups together with the non-adjacent carbon atoms to which they areattached form a substituted or unsubstituted 4-7-membered heterocyclyl;X is N or CR^(X); R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉alkyl); L is substituted or unsubstituted —O(C₁₋₆ alkyl)-, —(C₁₋₆alkyl)O—, —O(C₁₋₆ alkyl)O—, or —(C₁₋₉ alkyl)-; V is

wherein B is N, CH, or CR^(B); each R^(B) is independently selected fromhalogen, and substituted or unsubstituted C₁₋₆ alkyl; R^(C) is halogen,CF₃ or SF₅; R⁵ and R⁶ are C₁₋₃ alkyl, or R⁵ and R⁶, together with thecarbon atom to which they are attached, form a substituted orunsubstituted C₃₋₆ cycloalkyl or a 3-6 membered heterocyclyl; and b is0-2.
 2. The compound of claim 1, wherein n is 0, a is 1, and R² and R³are both H.
 3. The compound of claim 1, wherein each R⁴ is independentlyselected from methyl and CF₃.
 4. The compound of claim 1, wherein m is0, 1, 2, 3 or
 4. 5. The compound of claim 1, wherein X is N or CR^(X),where R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl). 6.The compound of claim 1, wherein L is substituted or unsubstituted—O(CH₂)_(p)—, —O(CH₂)_(p)O— or —(CH₂)_(p)—, and p is 1-4.
 7. Thecompound of claim 1, wherein B is CH or N.
 8. The compound of claim 1,wherein R^(C) is CF₃, Cl or SF₅.
 9. The compound of claim 1, wherein R⁵and R⁶ are methyl.
 10. The compound of claim 1, having formula II

or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof, wherein R^(N) is H; each R^(4m) is independentlyhydrogen or substituted or unsubstituted methyl, wherein thesubstituents, when present are selected from 1 to 5 halo; X is N orCR^(X); R^(X) is hydrogen, halogen, —O(C₁₋₆ alkyl) or —(C₁₋₉ alkyl); Lis substituted or unsubstituted —O(C₁₋₃ alkyl)-, —O(C₁₋₃ alkyl)O— or—(C₁₋₄ alkyl)-; V is

B is N or CH; R^(C) is halogen, CF₃ or SF₅; and R⁵ and R⁶ are C₁₋₃alkyl.
 11. The compound of claim 1, wherein the compound is selectedfrom2-((2S,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ6-sulfaneyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2S,4r,6R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2S,4s,6R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide,2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide,2-((R)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide,N-(3-Chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide,2-((R)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-((R)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetamide,2-((2R,4r,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)-5-fluorophenyl)acetamide,2-((S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((R)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-(4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,2-((2R,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,and2-((2R,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,or a pharmaceutically acceptable salt, tautomer, isotopolog, orstereoisomer thereof.
 12. A pharmaceutical composition comprising aneffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, and apharmaceutically acceptable carrier, excipient or vehicle.
 13. A methodfor the treatment of an androgen receptor mediated disease, the methodcomprising administering to a subject in need thereof an effectiveamount of the compound of claim 1, wherein the androgen mediated diseaseis prostate cancer.
 14. The method of claim 13, wherein the prostatecancer is castration resistant prostate cancer (CRPC).
 15. A method forthe treatment of an androgen receptor mediated disease, the methodcomprising administering to a subject in need thereof an effectiveamount of the pharmaceutical composition of claim 12, wherein theandrogen mediated disease is prostate cancer.
 16. The method of claim15, wherein the prostate cancer is castration resistant prostate cancer(CRPC).